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EP3439663B1 - Methods of treating pediatric cancers - Google Patents

Methods of treating pediatric cancers Download PDF

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Publication number
EP3439663B1
EP3439663B1 EP17719086.5A EP17719086A EP3439663B1 EP 3439663 B1 EP3439663 B1 EP 3439663B1 EP 17719086 A EP17719086 A EP 17719086A EP 3439663 B1 EP3439663 B1 EP 3439663B1
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Prior art keywords
liquid formulation
pediatric
cancer
compound
crystalline form
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EP17719086.5A
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German (de)
English (en)
French (fr)
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EP3439663A1 (en
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Michael Cox
Nisha NANDA
Mark Reynolds
Steven A. Smith
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Loxo Oncology Inc
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Loxo Oncology Inc
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Priority to SI201731550T priority Critical patent/SI3439663T1/sl
Priority to HRP20241295TT priority patent/HRP20241295T1/hr
Priority to RS20241058A priority patent/RS65988B1/sr
Priority to MA44612A priority patent/MA44612B1/fr
Publication of EP3439663A1 publication Critical patent/EP3439663A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (Formula ( I )) and pharmaceutically acceptable salts thereof, for example the hydrogen sulfate salt, a crystalline form of the hydrogen sulfate salt, which exhibit Trk family protein tyrosine kinase inhibition, for use in the treatment of pediatric cancers.
  • pharmaceutically acceptable salts thereof for example the hydrogen sulfate salt, a crystalline form of the hydrogen sulfate salt, which exhibit Trk family protein tyrosine kinase inhibition, for use in the treatment of pediatric cancers.
  • Infantile fibrosarcoma is a rare pediatric cancer typically presenting in the first two years of life. Surgical resection can be curative and chemotherapy is active against gross residual disease. However, when recurrences occur, therapeutic options are often limited.
  • Trk's are the high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT).
  • the Trk receptor family has three members - TrkA, TrkB and TrkC.
  • the neurotrophins are (i) nerve growth factor (NGF) which activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 which activates TrkC.
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • Trk-3 which activates TrkC.
  • Trk's are widely expressed in neuronal tissue and are implicated in the maintenance, signaling and survival of neuronal cells ( Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272-280 ).
  • Trk's overexpression, activation, amplification and/or mutation of Trk's are associated with many cancers including neuroblastoma ( Brodeur, G. M., Nat. Rev. Cancer 2003, 3, 203-216 ), ovarian cancer ( Davidson., B. et al., Clin. Cancer Res. 2003, 9, 2248-2259 ), breast cancer ( Kruettgen et al., Brain Pathology 2006, 16: 304-310 ), prostate cancer ( Dionne et al., Clin. Cancer Res.
  • pancreatic cancer Dang et al., Journal of Gastroenterology and Hepatology 2006, 21(5): 850-858 ), multiple myeloma ( Hu et al., Cancer Genetics and Cytogenetics 2007, 178: 1-10 ), astrocytoma amd medulloblastoma ( Kruettgen et al., Brain Pathology 2006, 16: 304-310 ), glioma ( Hansen et al., Journal of Neurochemistry 2007, 103: 259-275 ), melanoma ( Nakagawara, A. (2001) Cancer Letters 169:107-114 ; Meyer, J. et al.
  • Trk inhibitors are efficacious in both inhibiting tumor growth and stopping tumor metastasis.
  • non-selective small molecule inhibitors of TrkA, TrkB, TrkC and Trk/Fc chimeras were efficacious in both inhibiting tumor growth and stopping tumor metastasis ( Nakagawara, A. (2001) Cancer Letters 169:107-114 ; Meyer, J. et al. (2007) Leukemia, 1-10 ; Pierottia, M.A. and Greco A., (2006) Cancer Letters 232:90-98 ; Eric Adriaenssens, E. et al. Cancer Res (2008) 68:(2) 346-351 ). Therefore, an inhibitor of the Trk family of kinases is expected to have utility in the treatment of cancer.
  • inhibitors of the Trk/neurotrophin pathway have been demonstrated to be effective in numerous pre-clinical animal models of pain.
  • antagonistic NGF and TrkA antibodies for example, RN-624 have been shown to be efficacious in inflammatory and neuropathic pain animal models and in human clinical trials ( Woolf, C.J. et al. (1994) Neuroscience 62,327-331 ; Zahn, P.K. et al. (2004) J. Pain 5, 157-163 ; McMahon, S. B. et al., (1995) Nat. Med. 1, 774-780 ; Ma, Q. P. and Woolf, C. J. (1997) Neuroreport 8, 807-810 ; Shelton, D. L.
  • NGF secreted by tumor cells and tumor invading macrophages directly stimulates TrkA located on peripheral pain fibers.
  • Using various tumor models in both mice and rats it was demonstrated that neutralizing NGF with a monoclonal antibody inhibits cancer related pain to a degree similar or superior to the highest tolerated dose of morphine.
  • activation of the BDNF/TrkB pathway has been implicated in numerous studies as a modulator of various types of pain including inflammatory pain ( Matayoshi, S., J. Physiol. 2005, 569:685-95 ), neuropathic pain ( Thompson, S.W., Proc. Natl. Acad. Sci.
  • TrkA and TrkB kinases may serve as a mediator of NGF driven biological responses, inhibitors of TrkA and/or other Trk kinases may provide an effective treatment for chronic pain states.
  • the current treatment regimens for pain conditions utilize several classes of compounds.
  • the opioids such as morphine
  • Non-steroidal anti-inflammatory analgesics NSAIDs, such as COX-1 or COX-2 types
  • COX-1 inhibitors can cause ulcers of the mucosa. Accordingly, there is a continuing need for new and more effective treatments for the relief of pain, especially chronic pain.
  • inhibition of the neurotrophin/Trk pathway has been shown to be effective in treatment of pre-clinical models of inflammatory diseases.
  • inhibition of the neurotrophin/Trk pathway has been implicated in preclinical models of inflammatory lung diseases including asthma ( Freund-Michel, V; Frossard, N.; Pharmacology & Therapeutics (2008), 117(1), 52-76 ), interstitial cystitis ( Hu Vivian Y; et. al. The Journal of Urology (2005), 173(3), 1016-21 ), inflammatory bowel diseases including ulcerative colitis and Crohn's disease ( Di Mola, F. F, et.
  • the neurotrophin/Trk pathway has also been implicated in the etiology of neurodegenerative diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease ( Sohrabji, Farida; Lewis, Danielle K. Frontiers in Neuroendocrinology (2006), 27(4), 404-414 ). Modulation of the neutrophin/Trk pathway may have utility in treatment of these and related diseases.
  • TrkA receptor is also thought to be critical to the disease process in the infection of the parasitic infection of Trypanosoma cruzi (Chagas disease) in human hosts ( de Melo-Jorge, M. et al. Cell Host & Microbe (2007), 1(4), 251-261 ). Thus, TrkA inhibition may have utility in treating Chagas disease and related protozoan infections.
  • Trk inhibitors may also find use in treating disease related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.
  • Bone metastases are a frequent complication of cancer, occurring in up to 70 percent of patients with advanced breast or prostate cancer and in approximately 15 to 30 percent of patients with carcinoma of the lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney.
  • Osteolytic metastases can cause severe pain, pathologic fractures, life threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. For these reasons, bone metastasis is a serious and costly complication of cancer. Therefore, agents that can induce apoptosis of proliferating osteoblasts would be highly advantageous.
  • TrkA and TrkC receptors have been observed in the bone forming area in mouse models of bone fracture ( K. Asaumi, et al., Bone (2000) 26(6) 625-633 ). In addition, localization of NGF was observed in almost all bone forming cells (K. Asaumi, et al.). Recently, it was demonstrated that a pan-Trk inhibitor inhibits the tyrosine signaling activated by neurotrophins binding to all three of the Trk receptors in human hFOB osteoblasts (J. Pinski, et al., (2002) 62, 986-989). These data support the rationale for the use of Trk inhibitors for the treatment of bone remodeling diseases, such as bone metastases in cancer patients.
  • Trk kinases Several classes of small molecule inhibitors of Trk kinases said to be useful for treating pain or cancer are known ( Expert Opin. Ther. Patents (2009) 19(3 )).
  • PCT Patent Publication No. WO 2008/058126 discloses pyrazolo[1,5-a]pyrimidine compounds bearing a phenyl group at the 3-position. These compounds are asserted to be Pim-kinase inhibitors.
  • PCT Patent Publication Nos. WO 2010/033941 , WO 2010/048314 , WO 2011/006074 , and WO 2011/146336 disclose compounds which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
  • WO 2010/048314 discloses in Example 14A a hydrogen sulfate salt of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide.
  • WO 2010/048314 does not disclose the particular form of the hydrogen sulfate salt described herein when prepared according to the method of Example 14A in that document.
  • WO 2010/048314 does not disclose crystalline form (I-HS) as described below.
  • WO 2014/071358 describes novel NTRK1 fusion molecules, detection reagents, and uses and kits for evaluating, identifying, assessing and/or treating a subject having a cancer.
  • WO 2015/039006 describes methods relating to the treatment of cancer in subjects with genetic fusions of NTRK1.
  • the present invention relates to a liquid formulation for use in a method of treating a pediatric cancer in a subject in need thereof, wherein the formulation comprises a therapeutically effective amount of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I):
  • the subject is an infant, child, or adolescent.
  • the subject is an infant.
  • the pediatric cancer is a mesenchymal cancer.
  • the mesenchymal cancer can be selected from the group consisting of: pediatric nephroma, congenital fibrosarcoma (CFS), pediatric high-grade glioma (HGG), mesenchymal cancers (infant fibrosarcoma (IF), congenital mesoblastic nephroma, congenital infantile fibrosarcoma (CIFS); pilocytic astrocytoma, brain tumors, pediatic acute leukemia, Ph-like acute lymphoblastic leukemia, cellular congenital mesoblastic nephroma (CMN); infantile fibrosarcoma, pediatric high-grade glioma (HGG), diffuse intrinsic pontine gliomas (DIPGs), non-brainstem HGGs (NBS-HGGs), anaplastic large cell lymphoma (ALCL), non-Hodgkin's lymphoma
  • CFS con
  • the pediatric cancer is a fibrosarcoma such as infantile fibrosarcoma.
  • the pediatric cancer is a glioma.
  • the pediatric cancer is selected from the group consisting of: pediatric high-grade glioma (HGG), diffuse intrinsic pontine gliomas (DIPGs), and on-brainstem HGGs (NBS-HGGs).
  • the pediatric cancer is an extracranial solid tumor.
  • the pediatric cancer is selected from the group consisting of: neuroblastoma, nephroblastoma (e.g., Wilm's tumor), rhabdomyosarcoma and hepatoblastoma
  • the cancer is mediated by TrkA. In some embodiments, the cancer is mediated by TrkB. In some embodiments, the cancer is mediated by TrkC. In some embodiments, the cancer is mediated by TrkA, TrkB, TrkC, or combinations thereof.
  • surgical resection has failed to inhibit progression of the fibrosarcoma in the subject.
  • chemotherapy has failed to inhibit tumor progression in the subject.
  • the chemotherapy comprises administering at least one of vincristine, actinomycin-D, cyclophosphamide, ifosfamide, etoposide, or doxorubicin.
  • the chemotherapy including administering vincristine, actinomycin-D, and cyclophosphamide has failed to inhibit tumor progression in the subject.
  • the chemotherapy including administering ifosfamide and doxorubicin has failed to inhibit tumor progression in the subject.
  • the subject has a cancer that is ETV6-NTRK3 fusion positive.
  • the compound of formula (I) is a pharmaceutically acceptable salt.
  • the compound of formula (I) can be a hydrogen sulfate salt.
  • the compound of formula (I) is provided as a crystalline form.
  • the crystalline form can have the formula (I-HS):
  • the compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof is present in the liquid formulation in an amount from about 1.5 wt.% to about 2.5 wt.%.
  • the compound of formula (I), the pharmaceutically acceptable salt thereof, or the combination thereof has a concentration of about 20 mg/mL in the liquid formulation.
  • the solubilizing agent can include a ⁇ -cyclodextrin selected from the group consisting of a hydroxy alkyl- ⁇ -cyclodextrin, a sulfoalkyl ether- ⁇ -cyclodextrin, and combinations thereof.
  • the solubilizing agent includes hydroxypropyl- ⁇ -cyclodextrin.
  • the solubilizing agent is present in the liquid formulation in an amount of about 5 wt.% to about 35 wt.%.
  • the solubilizing agent can be present in the liquid formulation in an amount of about 13 wt.% to about 17 wt.%.
  • the formulation has a pH of about 3 to about 4. In some embodiments, the formulation has a pH of about 3.5.
  • the pH of the liquid formulation is adjusted.
  • the formulation includes a base.
  • the base can include one or more of a citrate, a lactate, a phosphate, a maleate, a tartarate, a succinate, an acetate, a carbonate, and a hydroxide.
  • the formulation includes at least one of lithium lactate, sodium lactate, potassium lactate, calcium lactate, lithium phosphate, sodium phosphate, potassium phosphate, calcium phosphate, lithium maleate, sodium maleate, potassium maleate, calcium maleate, lithium tartarate, sodium tartarate, potassium tartarate, calcium tartarate, lithium succinate, sodium succinate, potassium succinate, calcium succinate, lithium acetate, sodium acetate, potassium acetate, calcium acetate, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, or combinations thereof.
  • the base includes a citrate.
  • the citrate can include at least one of lithium citrate monohydrate, sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, lithium citrate dihydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate, lithium citrate trihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, lithium citrate tetrahydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, lithium citrate pentahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, lithium citrate hexahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, lithium citrate heptahydrate, sodium citrate heptahydrate, potassium citrate heptahydrate, or calcium citrate heptahydrate.
  • the liquid formulation includes at least one of sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, sodium citrate heptahydrate, potassium citrate heptahydrate, or calcium citrate heptahydrate.
  • the base includes sodium citrate dihydrate.
  • the formulation includes about 0.1 wt.% to about 5 wt.% of a base such as citrate (e.g., sodium citrate dihydrate).
  • a base such as citrate (e.g., sodium citrate dihydrate).
  • the liquid formulation can further include a sweetener.
  • the sweetener includes a sugar.
  • the sugar can include sucrose.
  • the sweetener includes an intense sweetener.
  • the intense sweetener can include sucralose.
  • the sweetener is present in the liquid formulation in an amount of about 30 wt.% to about 70 wt.%.
  • the sweetener can be present in the liquid formulation in an amount of about 45 wt.% to about 55 wt.%.
  • the liquid formulation can further include a bitterness masking agent.
  • the bitterness masking agent is present in the liquid formulation in an amount of about 0.01 wt.% to about 2 wt.%.
  • the bitterness masking agent can be present in the liquid formulation in an amount of about 0.2 wt.% to about 0.5 wt.%.
  • the liquid formulation can further include a flavoring agent.
  • the flavoring agent can include at least one of a natural flavoring agent, a natural fruit flavoring agent, an artificial flavoring agent, an artificial fruit flavoring agent, or a flavor enhancer.
  • the flavoring agent is present in the liquid formulation in an amount of about 0.01 wt.% to about 2 wt.%.
  • the flavoring agent can be present in the liquid formulation in an amount of about 0.01 wt.% to about 0.1 wt.%.
  • the liquid formulation further includes a coloring agent.
  • the liquid formulation is prepared from a pharmaceutically acceptable salt of the compound of formula (I).
  • the liquid formulation can be prepared from the hydrogen sulfate salt of the compound of formula (I).
  • a liquid formulation as provided herein can be prepared from a pharmaceutically acceptable salt of the compound of formula (I) such as the hydrogen sulfate salt.
  • the liquid formulation is prepared from a crystalline form of the compound of formula (I).
  • the crystalline form can have the formula (I-HS):
  • the crystalline form is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at 18.4 ⁇ 0.2, 20.7 ⁇ 0.2, 23.1 ⁇ 0.2, and 24.0 ⁇ 0.2. In some embodiments, the crystalline form is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at 10.7 ⁇ 0.2, 18.4 ⁇ 0.2, 20.7 ⁇ 0.2, 23.1 ⁇ 0.2, and 24.0 ⁇ 0.2. In some embodiments, the crystalline form is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at 10.7 ⁇ 0.2, 18.4 ⁇ 0.2, 19.2 ⁇ 0.2, 20.2 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 23.1 ⁇ 0.2, and 24.0 ⁇ 0.2.
  • the crystalline form is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at 10.7 ⁇ 0.2, 15.3 ⁇ 0.2, 16.5 ⁇ 0.2, 18.4 ⁇ 0.2, 19.2 ⁇ 0.2, 19.9 ⁇ 0.2, 20.2 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 22.1 ⁇ 0.2, 23.1 ⁇ 0.2, 24.0 ⁇ 0.2. 24.4 ⁇ 0.2, 25.6 ⁇ 0.2, 26.5 ⁇ 0.2, 27.6 ⁇ 0.2, 28.2 ⁇ 0.2, 28.7 ⁇ 0.2, 30.8 ⁇ 0.2, and 38.5 ⁇ 0.2.
  • the formulation has a pH of about 3 to about 4.
  • the base comprises sodium citrate dihydrate.
  • the liquid formulation comprises a compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof;
  • the liquid formulation comprises a compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof;
  • the liquid formulation comprises a compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof;
  • the liquid formulation comprises a compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof;
  • the liquid formulation is an oral liquid formulation.
  • the compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof is administered in 28-day cycles. In some embodiments, the compound is administered in a dosage calculated to be equal to the exposure of an adult taking the compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof, at a dose of 100 mg twice a day.
  • the present disclosure relates to liquid formulations including (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (formula (I)), pharmaceutically acceptable salts thereof, for example the hydrogen sulfate salt, a crystalline form of the hydrogen sulfate salt, for use in methods of treating pediatric cancers.
  • a patient is a pediatric patient (i.e., a patient under the age of 21 years at the time of diagnosis or treatment).
  • the term "pediatric” can be further divided into various subpopulations including: neonates (from birth through the first 28 days of life); infants (29 days of age to less than two years of age); children (two years of age to less than 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996 ; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002 ; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994 .
  • the patient is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday).
  • the patient is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.
  • the method further includes performing a morphological diagnosis prior to administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a combination thereof.
  • the method can further include performing molecular testing prior to administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a combination thereof.
  • the method includes performing morphological diagnosis and molecular testing prior to administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a combination thereof.
  • Some embodiments include the treatment of a Trk-associated cancer in a pediatric subject, which can be treated by inhibiting TrkA, TrkB and/or TrkC kinases, e.g., an infant, child, or adolescent.
  • TrkA, TrkB, and TrkC The Trk family of neurotrophin receptors, TrkA, TrkB, and TrkC (encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, differentiation and survival of neurons.
  • Dysregulation in a NTRK gene, a Trk protein, or expression or activity, or level of the same such as translocations involving the NTRK kinase domain, mutations involving the TRK ligand-binding site, amplifications of a NTRK gene, Trk mRNA splice variants, and overexpression of a NTRK gene (e.g., caused by Trk autocrine/paracrine signaling) are described in a diverse number of tumor types and may contribute to tumorigenesis.
  • Translocations in NTRK1, NTRK2, and NTRK3 that lead to the production of constitutively-active TrkA, TrkB, and TrkC fusion proteins are oncogenic and prevalent in a wide array of tumor types.
  • the dysregulation in a NTRK gene, a Trk protein, or expression or activity, or level of the same includes overexpression of a wild-type NTRK1, NTRK2, or NTRK3 gene (e.g., leading to autocrine activation).
  • the dysregulation in a NTRK gene, a Trk protein, or expression or activity, or level of the same includes overexpression, activation, amplification, or mutation in a chromosomal segment comprising the NTRK1, NTRK2, or NTKR3 gene or a portion thereof.
  • the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same includes one or more chromosome translocations or inversions resulting in NTRK1, NTRK2, or NTRK3 gene fusions, respectively.
  • the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same is a result of genetic translocations in which the expressed protein is a fusion protein containing residues from a non-TrkA partner protein and TrkA, a non-TrkB partner protein and TrkB, or a non-TrkC partner protein and TrkC proteins, and include a minimum of a functional TrkA, TrkB, or TrkC kinase domain, respectively.
  • a TrkA fusion protein is one of the TrkA fusion proteins shown in Table 10. Additional rearrangements of NTRK were detected in pediatric patients having papillary thyroid carcinomas ( Sassolas et al., Thyroid 22:17-26, 2012 ). Table 10. Exemplary Trk Fusion Proteins and Cancers in Pediatric Subjects Fusion Protein Non-Trk Fusion Partner Pediatric Cancer References ETV6-NTRK3 ETS variant gene 6, aka TEL Pediatric nephroma; Bouhana et al., AACR 103 rd Annual Congenital fibrosarcoma (CFS); Meeting, 2012, Abstract No. 1798; Bourgeois et al., Am. J. Surg. Pathol.
  • ALK-negative inflammatory myofibroblastic tumors (IMT); Alassiri et al., Am J Surg Pathol., 2016 Aug;40(8):1051-61, 2016 . Nagasubramanian et al., Pediatr Blood Cancer., Aug;63(8):1468-70, 2016 .
  • Mammary Carcinoma e.g., Mammary Analogue Secretory Carcinoma, Secretory Breast Carcinoma
  • Hyrcza et al. Vol. 469, Supp. Supplement 1, pp. S17. Abstract Number: OFP-1997-7; 31st International Congress of the International Academy of Pathology and the 28th Congress of the European Society of Pathology, Cologne, Germany.
  • TPM3-NTRK1 TPM3- actin bingind protein Pediatric high-grade glioma (HGG), diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs); Anaplastic large cell lymphoma (ALCL) and non-Hodgkin's lymphoma (NHL); Pilocytic astrocytoma; pediatric papillary thyroid carcinoma, soft tissue sarcoma; spitzoid melanomal Wu et al., Nat.
  • BTBD1-NTRK3 Topoisomerase I-interacting protein Pediatric high-grade glioma (HGG), diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs) Wu et al., Nat. Genet. 46:444-450, 2014 .
  • VCL-NTRK2 Actin-binding protein vinculin Pediatric high-grade glioma (HGG), diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs) Wu et al., Nat. Genet. 46:444-450, 2014 .
  • HGG high-grade glioma
  • DIPGs diffuse intrinsic pontine gliomas
  • NBS-HGGs non-brainstem HGGs
  • TFG-NTRK1 "Trk-fused gene” Anaplastic large cell lymphoma (ALCL) and non-Hodgkin's lymphoma (NHL) Drexler et al., Leukemia 14:1533-1559, 2000 QKI-NTRK2 KH domain containing RNA binding Pilocytic astrocytoma Jones et al., Nat. Genet.
  • NACC2 -NTRK2 NACC family member 2 Pilocytic astrocytoma Jones et al., Nat. Genet. 45:927-932, 2013 .
  • TPR-NTRK1 TPR Pediatic papillary thyroid carcinoma Beimfohr et al., Int. J. Cancer 80:842-847, 1999 ; Prasad et al., Cancer 122:1097-1017, 2016 .
  • the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same includes one or more deletions, insertions, or point mutation(s) in a Trk protein. In some embodiments, the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same, includes a deletion of one or more residues from the TrkA protein, resulting in constitutive activity of the Trk kinase domain.
  • the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same includes at least one point mutation in a NTRK1 gene that results in the production of a TrkA protein that has one or more amino acid substitutions as compared to the wildtype TrkA protein (see, for example, the point mutations listed in Tables 11 and 12).
  • An exemplary wildtype TrkA polypeptide is SEQ ID NO: 1
  • an exemplary wildtype TrkB polypeptide is SEQ ID NO: 2
  • an exemplary TrkC polypeptide is SEQ ID NO: 3. Table 11.
  • TrkA Point Mutations Mutation Pediatric Cancer Reference C6773T, C7232T, C7301T TrkA neuroblastoma Scaruffi et al., Int. J. Oncol. 14:935-938, 1999 Table 12.
  • TrkA Point Mutations A Point Mutation Rationale Exemplary Isoform in which Mutation is Present (if known) R33W B NP 001007793.1 F A336E Near NGF Binding Site Reference TrkA sequence A337T Near NGF Binding Site Reference TrkA sequence R324Q or R324W Near NGF Binding Site Unknown V420M Close to Membrane Reference TrkA sequence R444Q or R444W Close to Membrane Reference TrkA sequence G517R or G517V P-Loop Reference TrkA sequence K538A Activating Reference TrkA sequence V573M E Reference TrkA sequence F589L E Reference TrkA sequence G595R or G667C D Catalytic Domain Reference
  • Reference TrkA sequence R682S Activation Loop Reference TrkA sequence V683G Activation Loop Reference TrkA sequence R702C Exposed, may form face-to-face disulfide linked dimer Reference TrkA sequence Q627X C , Q597X C , Q633X C NP_001012331.1 G , NP_001007793.1 F , and Reference TrkA sequence, respectively
  • the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same includes a splice variation in a TrkA mRNA which results in an expressed protein that is an alternatively spliced variant of TrkA having at least one residue deleted (as compared to a wild-type TrkA protein) resulting in constitutive activity of the TrkA kinase domain.
  • an alternatively spliced form of TrkA with constitutive activity has deletions of exons 8, 9, and 11 resulting in an expressed protein missing residues 192-284 and 393-398 relative to TrkA Isoform 2, has a deletion of exon 10 in TrkA, or has a deletion in a NTRK1 gene that encodes a TrkA protein with a 75 amino acid deletion in the transmembrane domain ( Reuther et al., Mol. Cell Biol. 20:8655-8666, 2000 ).
  • Cancers identified as having dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same include: (A) Cancers wherein the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same, includes one or more chromosome translocations or inversions resulting in TrkA fusion proteins, e.g., including: Cancer Standard of Care Non-Small Cell Lung Cancer 2 radiotherapy (e.g., radioiodide therapy, external-beam radiation, or radium 223 therapy), chemotherapeutics as single agents (e.g., afatinib dimaleate, bevacizumab, carboplatin, cetuximab, cisplatin, crizotinib, erlotinib, gefitinib, gemcitabine, methotrexate, paclitaxe
  • Chemotherapeutics e.g., cyclophosphamide, doxorubicin, or vincristine
  • Pancreatic Carcinoma Chemotherapeutics as single agents (e.g., erlotinib, fluorouracil, gemcitabine, or mitomycin C) or combinations (e.g., gemcitabine-oxaliplatin) Melanoma 25 Chemotherapeutics (e.g., aldesleukin, dabrafenib, dacarbazine, interferon alfa-2b, ipilimumab, peginterferon alfa-2b, trametinib, or vemurafenib) Head and Neck Squamous Cell Carcino
  • the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same includes at least one point mutation in a NTRK1 gene that results in the production of a TrkB protein that has one or more amino acid substitutions as compared to the wildtype TrkB protein (see, for example, the point mutations listed in Table 13. Table 13.
  • the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same includes at least one point mutation in a NTRK1 gene that results in the production of a TrkC protein that has one or more amino acid substitutions as compared to the wildtype TrkC protein (see, for example, the point mutations listed in Table 14. Table 14.
  • TrkC Point Mutations A Point Mutation Rationale Exemplary Isoform in which Mutation is Present (if known)
  • V603M C NP_001007157.1
  • D F617L C Reference TrkC sequence
  • G623R B,C Steric Hinderance Reference TrkC sequence
  • G696C or G696A or G696S C Reference TrkC sequence
  • a TRK-associated cancer has been identified as having one or more TRK inhibitor resistance mutations (that result in an increased resistance to a TRK inhibitor.
  • TRK inhibitor resistance mutations are listed in Tables 15-17. Table 15.
  • Exemplary TrkA Resistance Mutations Amino acid position 517 (e.g., G517R) Amino acid position 542 (e.g., A542V) Amino acid position 568 (e.g., Q568x) Amino acid position 573 (e.g., V573M) Amino acid position 589 (e.g., F589L, F589C) Amino acid position 595 (e.g., G595S, G595R 1 ) Amino acid position 599 (e.g., D596V) Amino acid position 600 (e.g., F600L) Amino acid position 602 (e.g., R602x) Amino acid position 646 (e.g., F
  • Amino acid position 545 e.g., G545R
  • Amino acid position 570 e.g., A570V
  • Amino acid position 596 e.g., Q596E, Q596P
  • Amino acid position 601 e.g., V601G
  • Amino acid position 617 e.g., F617L, F617C, F617I
  • Amino acid position 623 e.g., G623S, G623R
  • Amino acid position 624 e.g., D624V
  • Amino acid position 628 e.g., F628x
  • Amino acid position 630 e.g., R630K
  • Amino acid position 672 e.g., F672x
  • Amino acid position 682 e.g., C682Y, C682F
  • Amino acid position 683 e.g.
  • Amino acid position 545 e.g., G545R
  • Amino acid position 570 e.g., A570V
  • Amino acid position 596 e.g., Q596x
  • Amino acid position 601 e.g., V601
  • Amino acid position 617 e.g., F617x, F617L
  • Amino acid position 623 e.g., G623R 1
  • Amino acid position 624 e.g., D624V
  • Amino acid position 628 e.g., F628x
  • Amino acid position 630 e.g., R630x
  • Amino acid position 675 e.g., F675x
  • Amino acid position 685 e.g., C685Y, C684F
  • Amino acid position 686 e.g., L686V
  • Amino acid position 696 e.g., G696x,
  • the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same includes a splice variation in a TrkA mRNA which results in an expressed protein that is an alternatively spliced variant of TrkA having at least one residue deleted (as compared to a wild-type TrkA protein) resulting in constitutive activity of the TrkA kinase domain.
  • an alternatively spliced form of TrkA with constitutive activity is the TrkAIII splice variant and, e.g., is associated with neuroectodermal-derived tumors including Wilm's tumor, neuroblastoma, and medulloblastoma (see, e.g., U.S. Patent Publication No. 2015/0218132 ).
  • Trk gene is another type of dysregulation of a NTRK gene that is associated with a variety of different pediatric cancers.
  • overexpression of a Trk receptor has been observed in neuroectodermal-derived tumors including Wilm's tumor, neuroblastoma, and medulloblastoma (see, e.g., U.S. Patent Application Publication No.
  • NTRK1 expression has been detected in bilateral stage IV adrenal neuroblastoma with multiple skin metastases in a neonate (see, e.g., Yanai et al., J. Pediatr. Surg. 39:1782-1783, 2004 ).
  • a Trk-associated cancer is advanced solid and primary central nervous system tumors (e.g., advanced solid and primary central nervous system tumors that are refractory to standard therapy).
  • the cancer is a solid or central nervous system tumors (e.g., advanced solid or primary central nervous system tumor) that is refractory to standard therapy.
  • Cancers identified as having dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same include:
  • the dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same includes a translocation that results in the expression of a TrkA, TrkB, or TrkC fusion protein, e.g., one of the TrkA, TrkB, or TrkC fusion proteins shown in Table 10.
  • the Trk-associated cancer can be selected from the group consisting of: pediatric nephroma, congenital fibrosarcoma (CFS), pediatric high-grade glioma (HGG), mesenchymal cancers (infant fibrosarcoma (IF), congenital mesoblastic nephroma, congenital infantile fibrosarcoma (CIFS); pilocytic astrocytoma, brain tumors (e.g., glioglastomas), pediatic acute leukemia, Ph-like acute lymphoblastic leukemia, cellular congenital mesoblastic nephroma (CMN); infantile fibrosarcoma, pediatric high-grade glioma (HGG), diffuse intrinsic pontine gliomas (DIPGs), non-brainstem HGGs (NBS-HGGs), anaplastic large cell lymphoma (ALCL), non-Hodgkin's lymphoma (NHL), pediatric
  • the pediatric cancer can be a fibrosarcoma.
  • the pediatric cancer can be infantile fibrosarcoma.
  • the subject is an infant and the fibrosarcoma is infantile fibrosarcoma.
  • the pediatric cancer is a myofibroblastic/fibroblastic tumor.
  • the pediatric cancer can be a solid tumor or a primary CNS tumor.
  • the pediatric cancer can also be a congenital mesoblastic nephroma.
  • a compound of formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof is useful for treating Trk-associated cancers in pediatric patients.
  • the compounds provided herein can be used to treat infantile sarcoma, pediatric glioma, neuroblastoma, congenital mesoblastic nephroma, brain low-grade glioma, and pontine glioma.
  • the Trk-associated cancer is a glioma.
  • the Trk-associated cancer is selected from the group consisting of: pediatric high-grade glioma (HGG), diffuse intrinsic pontine gliomas (DIPGs), and on-brainstem HGGs (NBS-HGGs).
  • the pediatric subject has been identified or diagnosed as having a cancer with dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the pediatric subject has a tumor that is positive for dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same (e.g., as determined using a regulatory agency-approved assay or kit).
  • the pediatric subject can be a subject with a tumor(s) that is positive for dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the pediatric subject can be a subject whose tumors have dysregulation of a NTRK gene, a Trk protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the pediatric subject is suspected of having a Trk-associated cancer.
  • the pediatric subject has a clinical record indicating that the pediatric subject has a tumor that has dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same (and optionally the clinical record indicates that the pediatric subject should be treated with any of the compositions provided herein).
  • an assay used to determine whether the pediatric subject e.g., an infant, a child, or an adolescent
  • a sample e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a subject (e.g., a pediatric subject (e.g., an infant, a child, or an adolescent) suspected of having a Trk-associated cancer
  • a pediatric subject e.g., an infant, a child, or an adolescent having one or more symptoms of a Trk-associated cancer
  • a pediatric subject e.g., an infant, a child, or an adolescent
  • a pediatric subject e.g., an infant, a child, or an adolescent that has an increased risk of developing a Trk-associated cancer
  • next generation sequencing immunohis
  • the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.
  • Assays can utilize other detection methods known in the art for detecting dysregulation of a NTRK gene, a Trk protein, or expression or activity, or levels of the same (see, e.g., the references cited herein).
  • the subject e.g., a pediatric subject, e.g., an infant, child, or adolescent
  • a pediatric subject e.g., an infant, child, or adolescent
  • a Trk protein e.g., a Trk protein
  • level of the same e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the subject e.g., a pediatric subject, e.g., an infant, child, or adolescent
  • a tumor that is positive for dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject e.g., a pediatric subject, e.g., an infant, child, or adolescent
  • a subject with a tumor(s) that is positive for dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject e.g., a pediatric subject, e.g., an infant, child, or adolescent
  • the subject can be a subject whose tumors have dysregulation of a NTRK gene, a Trk protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject e.g., a pediatric subject, e.g., an infant, child, or adolescent
  • the subject e.g., a pediatric subject, e.g., an infant, child, or adolescent
  • a clinical record e.g., a computer-readable medium
  • the subject has a tumor that has dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same (and optionally the clinical record further indicates that the subject should be treated with any of the compositions provided herein).
  • a dose contains, per unit dosage unit, about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof.
  • a unit dosage unit of about 2 mg to about 4 mg is formulated for a one-month old patient.
  • a unit dosage unit of about 6 to about 18 mg (e.g., about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, or about 18 mg) is formulated for a two-month or older infant.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed.
  • the dosages are administered once daily (QD) or twice daily (BID).
  • the daily dosage of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a combination thereof in a liquid formulation as described herein may be varied over a wide range from 1.0 to 10,000 mg per day, or higher, or any range therein.
  • the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1000 mg/kg of body weight per day, or any range therein.
  • the range can be from about 0.5 to about 500 mg/kg of body weight per day, or any range therein.
  • the range can be from about 1.0 to about 250 mg/kg of body weight per day, or any range therein.
  • the range can be from about 0.1 to about 100 mg/kg of body weight per day, or any range therein.
  • the range may be from about 0.1 to about 50.0 mg/kg of body weight per day, or any amount or range therein.
  • the range may be from about 0.1 to about 15.0 mg/kg of body weight per day, or any range therein.
  • the range may be from about 0.5 to about 7.5 mg/kg of body weight per day, or any amount to range therein.
  • a liquid formulation as provided herein may be administered on a regimen of 1 to 4 times per day or in a single daily dose.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • the compounds and formulations provided herein are administered on a continuous 28-day schedule.
  • a single cycle of administration includes 28 days of continuous dosing.
  • Such dosing can be, for example, one daily or twice daily.
  • the methods provided can follow after surgical resection has failed to inhibit progression of the fibrosarcoma in the subject.
  • the methods provided herein can also follow after chemotherapy including administration of at least one of vincristine, actinomycin-D, cyclophosphamide, ifosfamide, etoposide, doxorubicin has failed to inhibit tumor progression in the subject.
  • the methods provided herein can follow after administration of at least one of vincristine, actinomycin-D, and cyclophosphamide has failed to inhibit tumor progression in the subject.
  • the methods provided herein can also follow after administration of at least one of ifosfamide and doxorubicin has failed to inhibit tumor progression in the subject.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof can be provided in a crystalline form.
  • a crystalline form of the compound of formula (I) can include the hydrogen sulfate salt of the compound of formula (I) in a stable polymorph form, hereinafter referred to as crystalline form (I-HS), which may be characterized, for example, by its X-ray diffraction pattern.
  • I-HS crystalline form
  • the crystalline form (I-HS) can be characterized by its X-ray powder diffraction pattern (XRPD).
  • XRPD X-ray powder diffraction pattern
  • the XRPD was carried out on a D5000 X-ray diffractometer with a CuK ⁇ 1, 0.1540562 nm long, fine focus sealed tube source from Siemens by scanning samples between 3 and 40 °2-theta at a step size of 0.0200 °2-theta and a time per step of 1 second.
  • the effective scan speed was 0.0200 °/s with an instrument voltage 40 kV and a current setting of 40 mA. Samples were analyzed using a divergence slit having a size of 2 mm in reflection mode under the following experimental conditions.
  • crystalline form has an XRPD pattern with at least the 20 characteristic peaks (2 ⁇ degrees ⁇ 0.3), as listed in Table 1.
  • Table 1. XRPD peaks of crystalline form (I-HS) Position [°2- ⁇ ] FWHM [°2- ⁇ ] d-spacing [ ⁇ ] Relative Intensity [%] 10.63 0.12 8.32 27.44 15.25 0.14 5.81 12.24 16.39 0.13 5.40 13.92 18.37 0.13 4.82 43.65 19.08 0.14 4.65 19.60 19.79 0.11 4.48 9.83 20.15 0.25 4.40 25.09 20.61 0.13 4.31 100.00 21.47 0.21 4.14 24.71 22.01 0.12 4.03 14.45 23.04 0.15 3.86 33.01 23.97 0.12 3.71 38.52 24.35 0.21 3.65 10.05 25.58 0.13 3.48 8.11 26.48 0.17 3.36 9.76 27.50 0.14 3.24 7.70 28.17 0.17 3.16 11.60 28.58 0.19 3.12 10.85 30.
  • the crystalline form (I-HS) has an XRPD pattern with at least the 8 characteristic peaks (2 ⁇ degrees ⁇ 0.3), which comprises peaks having a relative intensity greater than or equal to about 15%, as listed in Table 2.
  • Table 2. XRPD peaks of crystalline form (I-HS) Position [°2- ⁇ ] FWHM [°2- ⁇ ] d-spacing [ ⁇ ] Relative Intensity [%] 10.63 0.12 8.32 27.44 18.37 0.13 4.82 43.65 19.08 0.14 4.65 19.60 20.15 0.25 4.40 25.09 20.61 0.13 4.31 100.00 21.47 0.21 4.14 24.71 23.04 0.15 3.86 33.01 23.97 0.12 3.71 38.52
  • the crystalline form (I-HS) has an XRPD pattern with at least the 5 characteristic peaks (2 ⁇ degrees ⁇ 0.3), which comprises peaks having a relative intensity greater than or equal to about 25%, as listed in Table 3.
  • Table 3. XRPD peaks of crystalline form (I-HS) Position [°2- ⁇ ] FWHM [°2- ⁇ ] d-spacing [ ⁇ ] Relative Intensity [%] 10.63 0.12 8.32 27.44 18.37 0.13 4.82 43.65 20.61 0.13 4.31 100.00 23.04 0.15 3.86 33.01 23.97 0.12 3.71 38.52
  • the crystalline form (I-HS) has an XRPD pattern with at least the 4 characteristic peaks (2 ⁇ degrees ⁇ 0.3), which comprises peaks having a relative intensity greater than or equal to about 30%, as listed in Table 4.
  • Table 4 XRPD peaks of crystalline form (I-HS) Position [°2- ⁇ ] FWHM [°2- ⁇ ] d-spacing [ ⁇ ] Relative Intensity [%] 18.37 0.13 4.82 43.65 20.61 0.13 4.31 100.00 23.04 0.15 3.86 33.01 23.97 0.12 3.71 38.52
  • crystalline form (I-HS) has an XRPD pattern that is substantially the same XRPD pattern as shown in Figure 1 .
  • crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at about 18.4, 20.6, 23.0, and 24.0. In some embodiments, crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at about 10.6, 18.4, 20.6, 23.0, and 24.0. In some embodiments, crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at about 10.6, 18.4, 19.1, 20.2, 20.6, 21.5, 23.0, and 24.0.
  • crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at about 10.6, 15.3, 16.4, 18.4, 19.1, 19.8, 20.2, 20.6, 21.5, 22.0, 23.0, 24.0, 24.4, 25.6, 26.5, 27.5, 28.2, 28.6, 30.8, and 38.5.
  • crystalline form (I-HS) has an XRPD pattern that is substantially the same XRPD pattern as shown in Figure 8 .
  • crystalline form (I-HS) has an XRPD pattern with at least the 20 characteristic peaks (2 ⁇ degrees ⁇ 0.3), as listed in Table 1.
  • Table 5. XRPD peaks of crystalline form (I-HS) Position (°2 ⁇ ) Relative Intensity (%) 10.76 29.85 15.38 13.22 16.52 16.46 18.50 48.07 19.22 22.92 19.92 16.05 20.26 30.80 20.74 100.00 21.56 23.78 22.16 15.51 23.16 32.52 24.10 33.89 24.50 12.14 25.72 8.89 26.50 10.88 27.62 8.61 28.32 11.44 28.74 10.73 30.92 8.23 38.60 8.88
  • the crystalline form (I-HS) has an XRPD pattern with at least the 8 characteristic peaks (2 ⁇ degrees ⁇ 0.3), which comprises peaks having a relative intensity greater than or equal to about 15%, as listed in Table 6.
  • Table 6 XRPD peaks of crystalline form (I-HS) Position (°2 ⁇ ) Relative Intensity (%) 10.76 29.85 18.50 48.07 19.22 22.92 20.26 30.80 20.74 100.00 21.56 23.78 23.16 32.52 24.10 33.89
  • the crystalline form (I-HS) has an XRPD pattern with at least the 5 characteristic peaks (2 ⁇ degrees ⁇ 0.3), which comprises peaks having a relative intensity greater than or equal to about 25%, as listed in Table 7.
  • Table 7. XRPD peaks of crystalline form (I-HS) Position (°2 ⁇ ) Relative Intensity (%) 10.76 29.85 18.50 48.07 20.74 100.00 23.16 32.52 24.10 33.89
  • the crystalline form (I-HS) has an XRPD pattern with at least the 4 characteristic peaks (2 ⁇ degrees ⁇ 0.3), which comprises peaks having a relative intensity greater than or equal to about 30%, as listed in Table 8.
  • Table 8. XRPD peaks of crystalline form (I-HS) Position (°2 ⁇ ) Relative Intensity (%) 18.50 48.07 20.74 100.00 23.16 32.52 24.10 33.89
  • crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at about 18.5, 20.7, 23.2, and 24.1. In some embodiments, crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at about 10.8, 18.5, 20.7, 23.2, and 24.1. In some embodiments, crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at about 10.8, 18.5, 19.2, 20.3, 20.7, 21.6, 23.2, and 24.1.
  • crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at about 10.8, 15.4, 16.5, 18.5, 19.2, 19.9, 20.3, 20.7, 21.6, 22.2, 23.2, 24.1, 24.5, 25.7, 26.5, 27.6, 28.3, 28.7, 30.9, and 38.6.
  • crystalline feorm is characterized by having XRPD peaks (2 ⁇ degrees) as shown in Table 9. Table 9. XRPD peaks of crystalline form (I-HS) FIG. 1 FIG.
  • crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at 18.4 ⁇ 0.2, 20.7 ⁇ 0.2, 23.1 ⁇ 0.2, and 24.0 ⁇ 0.2. In some embodiments, crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at 10.7 ⁇ 0.2, 18.4 ⁇ 0.2, 20.7 ⁇ 0.2, 23.1 ⁇ 0.2, and 24.0 ⁇ 0.2. In some embodiments, crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at 10.7 ⁇ 0.2, 18.4 ⁇ 0.2, 19.2 ⁇ 0.2, 20.2 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 23.1 ⁇ 0.2, and 24.0 ⁇ 0.2.
  • crystalline form (I-HS) is characterized by having XRPD diffraction peaks (2 ⁇ degrees) at 10.7 ⁇ 0.2, 15.3 ⁇ 0.2, 16.5 ⁇ 0.2, 18.4 ⁇ 0.2, 19.2 ⁇ 0.2, 19.9 ⁇ 0.2, 20.2 ⁇ 0.2, 20.7 ⁇ 0.2, 21.5 ⁇ 0.2, 22.1 ⁇ 0.2, 23.1 ⁇ 0.2, 24.0 ⁇ 0.2. 24.4 ⁇ 0.2, 25.6 ⁇ 0.2, 26.5 ⁇ 0.2, 27.6 ⁇ 0.2, 28.2 ⁇ 0.2, 28.7 ⁇ 0.2, 30.8 ⁇ 0.2, and 38.5 ⁇ 0.2.
  • the 2-theta values of the X-ray powder diffraction patterns for crystalline form may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation, and so the values quoted are not to be construed as absolute.
  • the relative intensities of peaks may vary depending on orientation effects so that the intensities shown in the XRPD trace included herein are illustrative and not intended to be used for absolute comparison. Accordingly, it is to be understood that the phrase "substantially the same XRPD pattern as shown in Figure 1 or Figure 8 " means that for comparison purposes, at least 90% of the peaks shown in Figure 1 or Figure 8 are present.
  • the relative peak positions may vary ⁇ 0.3 degrees from the peak positions shown in Figure 1 or Figure 8 . It is to be further understood that for comparison purposes some variability in peak intensities from those shown in Figure 1 and Figure 8 is allowed.
  • FIG. 2 illustrates a simultaneous thermogravimetric/differential thermal analyzer (TG/DTA) profile of crystalline form (I-HS), according to one embodiment.
  • TG/DTA simultaneous thermogravimetric/differential thermal analyzer
  • the TG/DAT profile of crystalline form shows an initial weight loss of 0.8% between 27.4° Celsius to 182.4° Celsius, which is followed by 4.9% weight loss in the TG curve between 182.4° Celsius to 225.0° Celsius, also seen as an endotherm in the DTA curve. These weight losses could be decomposition of the material.
  • FIG. 3 illustrates a differential scanning calorimetry (DSC) profile of crystalline form (I-HS), according to one embodiment.
  • DSC analysis of the sample was performed using a Seiko DSC6200 differential scanning calorimeter (equipped with a cooler).
  • About 5 mg of crystalline form (I-HS) was weighed into an aluminum DSC pan and sealed non-hermetically with a pierced aluminum lid.
  • the sample pan was then loaded into a Seiko DSC6200 (equipped with a cooler), cooled, and held at 25° Celsius. Once a stable heat-flow response was obtained, the sample and reference were heated to 270° Celsius at a scan rate of 10° Celsius/min while monitoring the resulting heat flow response.
  • crystalline form has a DSC thermogram substantially as shown in Figure 3 .
  • substantially as shown in Figure 3 means that the temperatures of the endothermic event shown in Figure 3 can vary by about ⁇ 5 °C.
  • the DSC thermogram of the crystalline form (I-HS) indicates a small endothermic change in the baseline between 122.9° Celsius to 152.8° Celsius, followed by a sharp endotherm that corresponds to the melting of the crystalline form (I-HS) at an onset temperature of melting of 190.8° Celsius, a peak temperature of melting of 197.9° Celsius and a heat of melting of 2.415 mW.
  • the transition following the melting endotherm may be caused by the decomposition of the melted crystalline form (I-HS).
  • FIGS. 4A and 4B illustrate polarized light microscopy (PLM) images of crystalline form (I-HS) under (A) unpolarized and (B) unpolarized light, according to some embodiments.
  • the presence of crystallinity (birefringence) was determined using an Olympus BX50 polarizing microscope, equipped with a Motic camera and image capture software (Motic Images Plus 2.0). All images were recorded using the 20x objective.
  • the crystalline form (I-HS) exhibits birefringence when examined under polarized light without exhibiting a definite morphology or agglomerates.
  • FIG. 5 illustrates a dynamic vapor sorption (DVS) isotherm profile of crystalline form (I-HS), according to one embodiment.
  • I-HS dynamic vapor sorption
  • FIG. 5 illustrates a dynamic vapor sorption (DVS) isotherm profile of crystalline form (I-HS), according to one embodiment.
  • DVS dynamic vapor sorption
  • a sample of crystalline form (I-HS) was cycled through changing humidity conditions to determine its hygroscopicity. The sample was analyzed using a Surface Measurement System DVS-1 Dynamic Vapor Sorption System. About 10 mg of crystalline form (I-HS) was placed into a mesh vapor sorption balance pan and loaded into a dynamic vapor sorption balance as part of the Surface Measurement System. Data was collected in 1 minute intervals. Nitrogen was used as the carrier gas.
  • the sampled crystalline form (I-HS) was subjected to a ramping profile from 20-90% relative humidity (RH) at 10% increments, maintaining the sample at each step until a stable weight had been achieved (99.5% step completion). After completion of the sorption cycle, the sample was dried using the same procedure, but all the way down to 0% RH and finally taken back to the starting point of 20% RH. The weight change during the sorption/desorption cycles were plotted, allowing for the hygroscopic nature of the sample to be determined.
  • RH relative humidity
  • crystalline form (I-HS) appears to be non-hygroscopic. A small increase in mass of about 1.7% was observed between 0% and 90% RH during the sorption cycle. In addition, a very small hysteresis was observed between sorption and desorption cycles.
  • the XRPD pattern of crystalline form (I-HS) post DVS analysis (not shown) being similar to its pre-DVS XRPD pattern shown in FIG. 1 or FIG. 29 indicates that no change in the crystalline form (I-HS) occurred during DVS.
  • FIG. 6 illustrates an infrared (IR) spectroscopy profile of crystalline form (I-HS) for the compound of formula (I), according to one embodiment.
  • IR spectroscopy was carried out on a Bruker ALPHA P spectrometer. Sufficient material of crystalline form (I-HS) was placed onto the center of the plate of the spectrometer with a transmittance spectrum being obtained using a resolution of 4 cm -1 , a background scan time of 16 scans, a sample scan time of 16 scans, and collecting data from 4000 cm -1 to 400 cm -1 .
  • the observed IR spectrum of crystalline form (I-HS) is shown in FIG. 6 .
  • the crystalline form (I-HS) has a number of properties that make it surprisingly superior to the amorphous form of ( S )-N-(5-(( R )-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate (AM(HS)).
  • the crystalline form (I-HS) has properties which contribute to its manufacturability and production of a commercial product.
  • the crystalline form (I-HS) has better flow properties as compared to the amorphous API (AM(HS)) as evidenced by the Carr's and Hausner Index.
  • the crystalline form (I-HS) exhibits a Carr Index value of greater than 20%.
  • the crystalline form (I-HS) exhibits a Hausner ratio of less than 1.35 (e.g., a value of between about 1.26 to about 1.34). The differences in flow properties can make the development of a solid oral dosage form more difficult for the amorphous API vs. the crystalline API.
  • the crystalline form (I-HS) also evidenced better stability in an accelerated stability study conducted in an LDPE bag at 40 °C/75% RH for five weeks. While neither the AM(HS) or crystalline form (I-HS) exhibited a significant changes in chemical impurity levels over the course of the study, the study did reveal that the crystalline form (I-HS) has stable physicochemical properties.
  • the amorphous API on the other hand, converted into a crystalline form substantially similar to the crystalline form (I-HS) by XRPD, DSC, TGA, KF and polarized light microscopy. Additionally, the amorphous API changed to an agglomerated powder with reduced flow properties over the course of the stability testing.
  • the crystalline form (I-HS), as noted previously, is non-hygroscopic.
  • non-hygroscopic refers to a compound exhibiting less than a 2% weight gain at 25 °C and 80% RH after 24 to 48 hours (see, e.g., Example 10).
  • the AM(HS) compound was found to deliquesce upon exposure to humidity. Given this tendency, use of the AM(HS) compound would require significant handling precautions during storage and manufacture to prevent this change in form from occurring whereas the crystalline form (I-HS) requires no such precautions during manufacture of the API. This stability to humidity would also be expected to carry over to any solid oral dosage product prepared using the crystalline form (I-HS).
  • the crystalline form (I-HS) provides a significantly improved impurity profile versus the amorphous API.
  • the ability to control an impurity profile is important for patient safety, developing a repeatable manufacturing process, and meeting requirements by Regulatory agencies prior to use in humans.
  • the compounds provided herein including (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (formula (I)) and pharmaceutically acceptable salts thereof, for example the hydrogen sulfate salt, and further a novel crystalline form of the hydrogen sulfate salt (crystalline form (I-HS)), exhibit Trk family protein tyrosine kinase inhibition, and the compound, hydrogen sulfate salt, and crystalline form thereof can be used in the treatment of pain, inflammation, cancer, and certain infectious diseases.
  • Non-limiting examples of doses of crystalline form (I-HS) or a compound of formula (I) or a salt thereof, such as a hydrogen sulfate salt (e.g., see Example 14A of U.S. Patent No. 8,513,263 ) that can be administered to a pediatric subject (in any of the methods or uses described herein) are described herein.
  • Non-limiting examples of the frequency of administration of crystalline form (I-HS) or a compound of formula (I) or a salt thereof, such as a hydrogen sulfate salt (e.g., see Example 14A of U.S. Patent No. 8,513,263 ) to a pediatric subject (that can be used in any of the methods or uses described herein) are described herein.
  • compositions provided herein may be, for example, surgery, radiotherapy, chemotherapy, signal transduction inhibitors and/or monoclonoal antibodies.
  • crystalline form may be administered in combination with one or more agents selected from mitotic inhibitors, alkylating agents, anti-metabolites, antisense DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, cytostatic agents anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, and prenyl-protein transferase inhibitors.
  • agents selected from mitotic inhibitors, alkylating agents, anti-metabolites, antisense DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, cytostatic agents anti-androgens, targeted antibodies, H
  • crystalline form contains two centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic or diastereomeric mixture, or in an enantiomerically pure form.
  • stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • Crystalline form (I-HS) may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g., rectally or orally), the nose, lungs, musculature or vasculature, or transdermally or dermally.
  • Crystalline form (I-HS) may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
  • liquid formulation including a solubilizing agent and (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I): a pharmaceutically acceptable salt thereof, or a combination thereof.
  • the solubilizing agent includes at least one of a hydroxy alkyl- ⁇ -cyclodextrin (e.g., hydroxypropyl- ⁇ -cyclodextrin) or a sulfoalkyl ether- ⁇ -cyclodextrin (e.g., sulfobutyl ether- ⁇ -cyclodextrin).
  • the liquid the solubilizing agent can include hydroxypropyl- ⁇ -cyclodextrin.
  • the cyclodextrin is CAVASOL ® W7 HP (hydroxypropyl- ⁇ -cyclodextrin).
  • the cyclodextrin is KLEPTOSE ® HP (hydroxypropyl- ⁇ -cyclodextrin). In some embodiments, the cyclodextrin is CAVAMAX ® W7 ( ⁇ -cyclodextrin). In some embodiments, the cyclodextrin is CAPTISOL ® (sulfoalkyl ether- ⁇ -cyclodextrin). In some embodiments, the cyclodextrin is CAVASOL ® W7 M (methyll- ⁇ -cyclodextrin).
  • SEDDS are isotropic mixtures of oils, surfactants, solvents and cosolvents/surfactants, that can be used to improve the oral absorption of highly lipophilic drug compounds. See, e.g., Tarate, B. et al., Recent Patents on Drug Delivery & Formulation (2014) Vol. 8 .
  • the poly(ethylene glycol) molecule is a linear polymer.
  • the molecular weight of the linear chain PEG may be between about 1,000 Da and about 100,000 Da.
  • a linear chain PEG used herein can have a molecular weight of about 100,000 Da, 95,000 Da, 90,000 Da, 85,000 Da, 80,000 Da, 75,000 Da, 70,000 Da, 65,000 Da, 60,000 Da, 55,000 Da, 50,000 Da, 45,000 Da, 40,000 Da, 35,000 Da, 30,000 Da, 25,000 Da, 20,000 Da, 15,000 Da, 10,000 Da, 9,000 Da, 8,000 Da, 7,000 Da, 6,000 Da, 5,000 Da, 5,000 Da, 4,000 Da, 3,000 Da, 2,000 Da, or 1,000 Da.
  • the molecular weight of the linear chain PEG is between about 1,000 Da and about 50,000 Da. In some embodiments, the molecular weight of the linear chain PEG is between about 1,000 Da and about 40,000 Da. In some embodiments, the molecular weight of the linear chain PEG is between about 5,000 Da and about 40,000 Da. In some embodiments, the molecular weight of the linear chain PEG is between about 5,000 Da and about 20,000 Da.
  • the poly(ethylene glycol) molecule is a branched polymer.
  • the molecular weight of the branched chain PEG may be between about 1,000 Da and about 100,000 Da.
  • a branched chain PEG used herein can have a molecular weight of about 100,000 Da, 95,000 Da, 90,000 Da, 85,000 Da, 80,000 Da, 75,000 Da, 70,000 Da, 65,000 Da, 60,000 Da, 55,000 Da, 50,000 Da, 45,000 Da, 40,000 Da, 35,000 Da, 30,000 Da, 25,000 Da, 20,000 Da, 15,000 Da, 10,000 Da, 9,000 Da, 8,000 Da, 7,000 Da, 6,000 Da, 5,000 Da, 5,000 Da, 4,000 Da, 3,000 Da, 2,000 Da, and 1,000 Da.
  • the molecular weight of the branched chain PEG is between about 1,000 Da and about 50,000 Da. In some embodiments, the molecular weight of the branched chain PEG is between about 1,000 Da and about 40,000 Da. In some embodiments, the molecular weight of the branched chain PEG is between about 5,000 Da and about 40,000 Da. In some embodiments, the molecular weight of the branched chain PEG is between about 5,000 Da and about 20,000 Da.
  • the solubilizing agent can be present in the liquid formulation in an amount of about 5 wt.% to about 35 wt.%, about 10 wt.% to about 25 wt.%, about 10 wt.% to about 20 wt.%, or about 13 wt.% to about 17 wt.%.
  • the solubilizing agent can be present at about 5 wt.%, 7 wt.%, 10 wt.%, 13 wt.%, 15 wt.%, 17 wt.%, 20 wt.%, 23 wt.%, 26 wt.%, 30 wt.% or about 35 wt.%.
  • the solubilizing agent is present in the liquid formulation in an amount of 15 wt.%.
  • a buffer can be added to the liquid formulation to adjust the pH of the formulation to a desired pH.
  • a buffer can be added in an amount to adjust the pH of the formulation to a pH of about 2 to about 7, about 2.5 to about 5.5, or about 3 to about 4.
  • a buffer can be added in an amount to adjust the pH of the formulation to a pH of about 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, or about 7.0.
  • a buffer can be added in an amount to adjust the pH of the formulation to a pH of about 3.5.
  • the buffer includes a citrate buffer, a lactate buffer, a phosphate buffer, a maleate buffer, a tartrate buffer, a suucinate buffer, an acetate buffer, or a combination thereof.
  • the buffer includes lithium lactate, sodium lactate, potassium lactate, calcium lactate, lithium phosphate, sodium phosphate, potassium phosphate, calcium phosphate, lithium maleate, sodium maleate, potassium maleate, calcium maleate, lithium tartrate, sodium tartrate, potassium tartrate, calcium tartrate, lithium succinate, sodium succinate, potassium succinate, calcium succinate, lithium acetate, sodium acetate, potassium acetate, calcium acetate, or combinations thereof.
  • the buffer is a citrate buffer.
  • the citrate buffer can include at least one of lithium citrate monohydrate, sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, lithium citrate dihydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate, lithium citrate trihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, lithium citrate tetrahydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, lithium citrate pentahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, lithium citrate hexahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, lithium citrate heptahydrate, sodium citrate heptahydrate, potassium citrate heptahydrate, calcium citrate heptahydrate, or mixtures thereof.
  • the buffer can include sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, sodium citrate heptahydrate, potassium citrate heptahydrate, or calcium citrate heptahydrate.
  • the buffer includes sodium citrate dihydrate.
  • the buffer is present in the liquid formulation in an amount of about 0.1 wt.% to about 5 wt.%, about 0.3 wt.% to about 4 wt.%, about 0.5 wt.% to about 3.5 wt.%, about 0.6 wt.% to about 3 wt.%, 0.7 wt.% to about 2.5 wt.%, about 0.7 wt.% to about 2.0 wt.%, or about 0.7 wt.% to about 1.5 wt.%.
  • the buffer can be present in the liquid formulation in an amount of about 0.1 wt.%, 0.3 wt.%, 0.5 wt.%, 0.7 wt.%, 0.9 wt.%, 1.1 wt.%, 1.5 wt.%, 2.0 wt.%, 2.5 wt.%, 3.0 wt.%, 3.5 wt.%, 4.0 wt.%, or about 5 wt.%. In some embodiments, the buffer is present in the liquid formulation in an amount of about 0.9 wt.%.
  • the pH of the liquid formulation can be adjusted to a desired pH.
  • the pH of the formulation can be adjusted to a pH of about 3 to about 4.
  • the pH of the formulation is adjusted to a pH of about 3.5.
  • the liquid formulation includes a base.
  • the base is selected from a citrate, a lactate, a phosphate, a maleate, a tartrate, a succinate, an acetate, a carbonate, a hydroxide, or a combination thereof.
  • the base includes lithium lactate, sodium lactate, potassium lactate, calcium lactate, lithium phosphate, sodium phosphate, potassium phosphate, calcium phosphate, lithium maleate, sodium maleate, potassium maleate, calcium maleate, lithium tartrate, sodium tartrate, potassium tartrate, calcium tartrate, lithium succinate, sodium succinate, potassium succinate, calcium succinate, lithium acetate, sodium acetate, potassium acetate, calcium acetate, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, or combinations thereof.
  • the base includes a citrate.
  • the citrate can include at least one of lithium citrate monohydrate, sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, lithium citrate dihydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate, lithium citrate trihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, lithium citrate tetrahydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, lithium citrate pentahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, lithium citrate hexahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, lithium citrate heptahydrate, sodium citrate heptahydrate, potassium citrate heptahydrate, calcium citrate heptahydrate, or mixtures thereof.
  • the base can include sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, sodium citrate heptahydrate, potassium citrate heptahydrate, or calcium citrate heptahydrate.
  • the base includes sodium citrate dihydrate.
  • the base is present in the liquid formulation in an amount of about 0.1 wt.% to about 5 wt.%, about 0.3 wt.% to about 4 wt.%, about 0.5 wt.% to about 3.5 wt.%, about 0.6 wt.% to about 3 wt.%, 0.7 wt.% to about 2.5 wt.%, about 0.7 wt.% to about 2.0 wt.%, or about 0.7 wt.% to about 1.5 wt.%.
  • the base can be present in the liquid formulation in an amount of about 0.1 wt.%, 0.3 wt.%, 0.5 wt.%, 0.7 wt.%, 0.9 wt.%, 1.1 wt.%, 1.5 wt.%, 2.0 wt.%, 2.5 wt.%, 3.0 wt.%, 3.5 wt.%, 4.0 wt.%, or about 5 wt.%.
  • the base is present in the liquid formulation in an amount of about 0.9 wt.%.
  • the citrate is present in the liquid formulation in an amount of about 0.1 wt.% to about 5 wt.%, about 0.3 wt.% to about 4 wt.%, about 0.5 wt.% to about 3.5 wt.%, about 0.6 wt.% to about 3 wt.%, 0.7 wt.% to about 2.5 wt.%, about 0.7 wt.% to about 2.0 wt.%, or about 0.7 wt.% to about 1.5 wt.%.
  • the citrate can be present in the liquid formulation in an amount of about 0.1 wt.%, 0.3 wt.%, 0.5 wt.%, 0.7 wt.%, 0.9 wt.%, 1.1 wt.%, 1.5 wt.%, 2.0 wt.%, 2.5 wt.%, 3.0 wt.%, 3.5 wt.%, 4.0 wt.%, or about 5 wt.%.
  • the citrate is present in the liquid formulation in an amount of about 0.9 wt.%.
  • a sweetener can be added to the liquid formulation to make it less bitter or palatable, or both.
  • Sweeteners suitable for inclusion in the formulation can include, both natural and artificial sweeteners.
  • the sweetener is an artificial sweetener and can include intense or high-intensity sweeteners.
  • Intense sweeteners are commonly used as sugar substitutes or sugar alternatives as they are many times sweeter than sugar but contribute only a few to no calories when added to food.
  • Exemplary intense sweeteners include sorbitol, sucrose, saccharins such as sodium saccharin, cyclamates such as sodium cyclamates, aspartame, sucralose, thaumatin, and acesulfam K.
  • the sweetener is a natural sugar.
  • sugars such as monosaccharides, disaccharides and polysaccharides can be used in the liquid formulations provided herein.
  • the sugars can include xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch or corn syrup, and sugar alcohols such as sorbitol, xylitol, mannitol, glycerin, and combination thereof.
  • the liquid formulation further comprises a sweetener.
  • the sweetener can include a sugar.
  • the sweetener can include sucrose.
  • the sweetener can be ORA-SWEET ® , a sweetener that includes purified water, sucrose, glycerin, sorbitol, and flavoring; is buffered with citric acid and sodium phosphate; and is preserved with methylparaben and potassium sorbate.
  • the sweetener can also include an intense sweetener.
  • the intense sweetener can include sucralose.
  • the sweetener can be ORA-SWEET SF ® , a sugar free sweetener that includes purified water, glycerin, sorbitol, sodium saccharin, xanthan gum, and flavoring; is buffered with citric acid and sodium citrate; and is preserved with methylparaben (0.03%), potassium sorbate (0.1%), and propylparaben (0.008%).
  • ORA-SWEET SF ® a sugar free sweetener that includes purified water, glycerin, sorbitol, sodium saccharin, xanthan gum, and flavoring; is buffered with citric acid and sodium citrate; and is preserved with methylparaben (0.03%), potassium sorbate (0.1%), and propylparaben (0.008%).
  • the sweetener includes one or more of sucrose, glycerin, sorbitol, and flavoring. In some such embodiments, the sweetener further includes citric acid and sodium phosphate. In some such embodiments, the sweetener can include a preservative, such as methylparaben and potassium sorbate.
  • the sweetener includes sucrose, glycerin, sorbitol, flavoring, citric acid, sodium phosphate, methylparaben, and potassium sorbate. In some embodiments, the sweetener includes one or more of glycerin, sorbitol, sodium saccharin, xanthan gum, and flavoring.
  • the sweetener further includes citric acid and sodium citrate.
  • the sweetener includes a preservative, such as methylparaben, potassium sorbate, and propylparaben.
  • the sweetener can include glycerin, sorbitol, sodium saccharin, xanthan gum, flavoring, citric acid and sodium citrate, methylparaben (0.03%), potassium sorbate (0.1%), and propylparaben (0.008%).
  • the sweetener is present in the liquid formulation in an amount of about 30 wt.% to about 70 wt.%, about 35 wt.% to about 65 wt.%, about 40 wt.% to about 60 wt.%, or about 45 wt.% to about 55 wt.%.
  • the sweetener can be present in the liquid formulation in an amount of about 30 wt.%, 35 wt.%, 40 wt.%, 45 wt.%, 50 wt.%, 55 wt.%, 60 wt.%, 65 wt.%, or about 70 wt.%.
  • the sweetener is present in the liquid formulation in an amount of about 50 wt.%.
  • the liquid formulation further comprises a bitterness masking agent.
  • the bitterness masking agent can include 231a12 natural masking type flavor (Abelei ® ), 231a39 natural bitterness masking type flavor (Abelei ® ), bitterness masking flavor, nat (FONA ® ), and FINATECH Taste Modifier Flavor, Nat.
  • the bitterness masking agent can be present in the liquid formulation in an amount of about 0.01 wt.% to about 2 wt.%, about 0.1 wt.% to about 1.0 wt.%, or about 0.2 wt.% to about 0.5 wt.%.
  • the bitterness masking agent can be present in the liquid formulation in an amount of about 0.01 wt.%, 0.1 wt.%, 0.2 wt.%, 0.3 wt.%, 0.4 wt.%, 0.5 wt.%, 0.7 wt.%, 1.0 wt.%, 1.5 wt.%, or 2.0 wt.%.
  • the bitterness masking agent is present in the liquid formulation in an amount of about 0.4 wt.%.
  • a flavoring agent can be included in the liquid formulation so that the final formulation has a substantially non-bitter and palatable taste.
  • the flavoring agent can include at least one of a natural flavoring agent, a natural fruit flavoring agent, an artificial flavoring agent, an artificial fruit flavoring agent, flavor enhancers, or mixtures thereof. Exemplary flavoring agents can be found, for example in US CFR 21 ⁇ 172.515 (April 1, 2015).
  • the flavoring agent can include a FONATECH ® natural taste modifier flavoring agent.
  • the flavoring agent can be present in the liquid formulation in an amount of about 0.01 wt.% to about 2 wt.%, about 0.01 wt.% to about 0.1 wt.%, or about 0.2 wt.% to about 0.5 wt.%.
  • the flavoring agent can be present in an amount of about 0.01 wt.%, 0.1 wt.%, 0.2 wt.%, 0.3 wt.%, 0.4 wt.%, 0.5 wt.%, 0.7 wt.%, 1.0 wt.%, 1.5 wt.%, or 2.0 wt.%.
  • the flavoring agent can be present in the liquid formulation in an amount of about 0.5 wt.%.
  • the liquid formulation can also include a coloring agent.
  • the compounds may accordingly exist as enantiomers. Where the compounds possess two chiral centers, the compounds may additionally exist as diastereomers. That is, the compound of formula (I), in addition to having the desired configuration designated by the nomenclature "(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate" (hereinafter referred to as the (S,R) isomer), it may also be present in minor amounts as the isomer (R)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate (hereinafter referred to as the (S,R) isomer
  • the (S,R) isomer is present at an excess of greater than or equal to about 80%, more preferably at an excess of greater than or equal to about 90%, more preferably still at an excess of greater than or equal to about 95%, more preferably still at an excess of greater than or equal to about 98%, more preferably at an excess of greater than or equal to about 99%.
  • isolated form shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment.
  • the crystalline form (I-HS) is present as an isolated form.
  • substantially pure form shall mean that the mole percent of impurities in the isolated compound or crystalline form is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent.
  • the crystalline form (I-HS) is present as a substantially pure form.
  • the term "substantially free of other amorphous, polymorph or crystalline form(s)" when used to described crystalline form (I-HS) shall mean that mole percent of other amorphous, polymorph or crystalline form(s) of the isolated base of crystalline form (I-HS) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent.
  • the crystalline form (I-HS) is present as a form substantially free of other amorphous, polymorph or crystalline form(s).
  • polymorph and “polymorphic form” refer to different crystalline forms of a single compound. That is, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct solid state physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct solid state physical properties, such as different solubility profiles, dissolution rates, melting point temperatures, flowability, and/or different X-ray diffraction peaks. The differences in physical properties may affect pharmaceutical parameters such as storage stability, compressibility and density (which can be important in formulation and product manufacturing), and dissolution rate (which can be an important factor in bioavailability).
  • Techniques for characterizing polymorphic forms include, but are not limited to, X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), single-crystal X-ray diffractometry (XRD), vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurements, dissolution measurements, elemental analysis and Karl Fischer analysis.
  • XRPD X-ray powder diffractometry
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • XRD single-crystal X-ray diffractometry
  • vibrational spectroscopy e.g., infrared (IR) and Raman spectroscopy
  • NMR nuclear
  • amorphous means a solid in a solid state that is a non-crystalline state. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering.
  • the solid state form of a solid may be determined by polarized light microscopy, X-ray powder diffraction ("XRPD”), differential scanning calorimetry (“DSC”), or other standard techniques known to those of skill in the art.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. In some embodiments, pharmaceutically acceptable salts may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form.
  • Basic compounds are generally capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids.
  • Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, est
  • treating shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a disclosed compound to alleviate the symptoms or complications, or reduce the rate of progression of the disease, condition, or disorder.
  • prevention shall include (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of additional symptoms; and/or (d) delay or avoidance of the development of the disorder or condition.
  • Trk-associated cancer shall be defined to include cancers associated with or having dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same (e.g., any of types of dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same, described herein).
  • Trk-associated cancer is described herein.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, a patient is a pediatric patient (i.e. a patient under the age of 21 years at the time of diagnosis or treatment).
  • the term "pediatric” can be further divided into various subpopulations including: neonates (from birth through the first 28 days of life); infants (29 days of age to less than two years of age); children (two years of age to less than 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996 ; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002 ; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994 .
  • NTRK gene includes any of the NTRK genes described herein (e.g., a NTRK1, a NTRK2, or a NTRK3 gene).
  • wildtype or wild-type describes a nucleic acid (e.g., a NTRK gene or a Trk mRNA) or protein (e.g., a Trk protein) that is found in a subject (e.g., a pediatric subject, e.g., an infant, child, or adolescent) that does not have a Trk-associated cancer (and optionally also does not have an increased risk of developing a Trk-associated cancer or condition and/or is not suspected of having a Trk-associated cancer or condition) or is found in a cell or tissue from a subject (e.g., a pediatric subject, e.g., an infant, child, or adolescent) that does not have a Trk-associated cancer or condition (and optionally also does not have an increased risk of developing a Trk-associated cancer or condition and/or is not suspected of having a Trk-associated cancer or condition).
  • a subject e.g., a pediatric subject, e.g.,
  • regulatory agency is a country's agency for the approval of the medical use of pharmaceutical agents with the country.
  • regulatory agency is the U.S. Food and Drug Administration (FDA).
  • the phrase "dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same” is a genetic mutation (e.g., a NTRK gene translocation that results in the expression of a fusion protein, a deletion in a NTRK gene that results in the expression of a Trk protein that includes a deletion of at least one amino acid as compared to the wild-type Trk protein, or a mutation in a NTRK gene that results in the expression of a Trk protein with one or more point mutations, an alternative spliced version of a Trk mRNA that results in a Trk protein that results in the deletion of at least one amino acid in the Trk protein as compared to the wild-type Trk protein), or a NTRK gene duplication that results in overexpression of a Trk protein) or overexpression of a NTRK gene in a cell, that results in a pathogenic increase in the activity of a kinase domain of a Trk protein (e.
  • a dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same can be a mutation in a NTRK1, NTRK2, or NTRK3 gene that encodes a Trk protein that is constitutively active or has increased activity as compared to a protein encoded by a NTRK1, NTRK2, or NTRK3 gene that does not include the mutation.
  • a dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same can be the result of a gene translocation which results in the expression of a fusion protein that contains a first portion of TrkA, TrkB, or TrkC that includes a functional kinase domain, and a second portion of a partner protein (i.e., that is not TrkA, TrkB, or TrkC).
  • a gene encoding a fusion protein can include, e.g., the following exons of a wild-type NTRK1 gene: exons 10-19, exons 12-19, exons 12-19, exons 13-19, exons 14-19, or exons 15-19.
  • a gene encoding a fusion protein can include, e.g., the following exons of a wild-type NTRK2 gene: exons 12-21, exons 13-21, exons 15-21, exons 16-21, or exons 17-21.
  • a gene encoding a fusion protein can include, e.g., the following exons of a wild-type NTRK3 gene: exons 17-22 or exons 16-22.
  • Non-limiting examples of fusion proteins that are a result of a NTRK gene translocation are described in Table 10.
  • a dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same can, e.g., include a mutation(s) in a NTRK1, NTRK2, or NTRK3 gene that results in a TrkA, TrkB, or TrkC containing at least one (e.g., two, three, four, or five) point mutations (e.g., one of more of the point mutations listed in Table XX).
  • a dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same can be a mutation in a NTRK1, NTRK2, or NTRK3 gene that results in a deletion of one or more contiguous amino acids (e.g., at least two, at least three, at least four, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, at least 180, at least 190, at least 200, at least 210, at least 220, at least 230, at least 240, at least 250, at least 260, at least 270, at least 280, at least 290, at least 300, at least 310, at least 320, at least 330, at least 340, at least 350, at least 360
  • a dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same can include an alternate spliced form of a Trk mRNA, e.g., a TrkAIII spliced variant or an alternative spliced form of a TrkA mRNA that results in the production of a TrkA protein that lacks the amino acids encoded by exon 10.
  • an alternate spliced form of a Trk mRNA e.g., a TrkAIII spliced variant or an alternative spliced form of a TrkA mRNA that results in the production of a TrkA protein that lacks the amino acids encoded by exon 10.
  • a dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same includes an amplification of a NTRK gene (e.g., one, two, three, or four additional copies of the NTRK gene) that can result, e.g., in autocrine or overexpression of a NTRK gene in a cell.
  • the term "overexpression" is a term of art and is used to an increased level of transcription of a gene in a cell as compared to the level of transcription of the gene in a control cell (e.g., a non-cancerous cell of the same cell type).
  • Trk-associated cancer or tumor is a cancer that is associated with dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same (e.g., a cancer that is associated with at least one example (e.g., two, three, four, or five examples) of dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same, described herein).
  • mammal refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
  • a therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • a therapeutically effective amount when administered to a subject in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition, or disorder which can be treated with an inhibitor of TrkA and/or TrkB, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the amount of crystalline form (I-HS) that will correspond to such a therapeutically effective amount will vary depending upon factors such the disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the term “about” is used herein to mean approximately, in the region of, roughly, or around.
  • the term “about” modifies that range by extending the boundaries above and below the numerical values set forth.
  • the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%.
  • the term "about" preceding one or more peak positions in an X-ray powder diffraction pattern means that all of the peaks of the group which it precedes are reported in terms of angular positions (two theta) with an allowable variability of ⁇ 0.3°.
  • the variability of ⁇ 0.3° is intended to be used when comparing two powder X-ray diffraction patterns.
  • a diffraction pattern peak from one pattern is assigned a range of angular positions (two theta) which is the measured peak position ⁇ 0.3° and if those ranges of peak positions overlap, then the two peaks are considered to have the same angular position. For example, if a peak from one pattern is determined to have a position of 11.0°, for comparison purposes the allowable variability allows the peak to be assigned a position in the range of 10.7°-11.3°.
  • determining proper dosages for pediatric patients can be determined using known methods, including weight, age, and models such as Simcyp ® Pediatric Simulation modeling (CERTARA, Princeton, New Jersey) which can be used to establish a pharmacokinetic approach for dosing that takes into account patient age, ontogeny of the clearance pathways that a compound of formula (I) , a pharmaceutically acceptable salt thereof, or a combination thereof, and body surface area (BSA).
  • CERTARA Simcyp ® Pediatric Simulation modeling
  • reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product.
  • a reaction step as disclosed herein may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • a reagent or reagent class/type e.g. base, solvent, etc.
  • the individual reagents are independently selected for each reaction step and may be the same of different from each other.
  • the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.
  • reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe or addition funnel.
  • HPLC high performance liquid chromatography
  • Amorphous hydrogen sulfate salt of compound of formula (I) was prepared as described in Example 14A in WO 2010/048314 (see Example 3).
  • the XRPD patterns of the two different lots of amorphous material prepared by this method are show in FIG. 7 .
  • the above method further comprises: (b1) seeding the solution from step (a) with (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate at room temperature and allowing the solution to stir until a slurry forms.
  • the base is an amine base, such as triethylamine.
  • the base is an alkali metal base, such as an alkali metal carbonate, such as potassium carbonate.
  • Step A Preparation of sodium pyrazolo[1,5-a]pyrimidin-5-olate: A solution of 1H-pyrazol-5-amine and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1.05 equiv.) were charged to a round bottom flask outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an N 2 adaptor for positive N 2 pressure control. Under mechanical stirring the solids were suspended with 4 vol. (4 mL/g) of absolute EtOH under a nitrogen atmosphere, then charged with 2.1 equivalentsof NaOEt (21 wt% solution in EtOH), and followed by line-rinse with 1 vol.
  • Step B Preparation of 3-nitropyrazolo[1,5-alpyiimidin-5(4H)-one: A tared round bottom flask was charged with sodium pyrazolo[1,5-a]pyrimidin-5-olate that was dissolved at 40-45° Celsius in 3.0 vol. (3.0 mL/g) of deionized water, and then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4 x weight of starting material was observed (1.4 vol/1.4 mL/g deionized water content).
  • a round bottom vessel outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an N 2 adaptor for positive N 2 pressure control was charged with 3 vol. (3 mL/g, 10 equiv) of >90 wt% HNO 3 and cooled to about 10° Celsius under a nitrogen atmosphere using external ice-water cooling bath under a nitrogen atmosphere.
  • the HNO 3 solution was charged with the 1.75-1.95 volumes of a deionized water solution of sodium pyrazolo[1,5-a]pyrimidin-5-olate (1.16-1.4 mL DI water/g of sodium pyrazolo[1,5-a]pyrimidin-5-olate) at a rate to maintain 35-40° Celsius internal temperature under cooling.
  • Two azeotropes were observed without any ethyl nitrate fumes.
  • the azeotrope flask, the transfer line (if applicable) and the addition funnel were rinsed with 2 x 0.1 vol. (2 x 0.1 mL/g) deionized water added to the reaction mixture.
  • Step C Preparation of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine: 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one was charged to a round bottom flask outfitted with a mechanical stirrer, a heating mantle, a reflux condenser, a J-Kem temperature probe and an N 2 adaptor for positive N 2 pressure control. Under mechanical stirring the solids were suspended with 8 volumes (8 mL/g) of CH 3 CN, and then charged with 2,6-lutitine (1.05 equiv) followed by warming the slurry to about 50° Celsius. Using a pressure equalizing addition funnel, the mixture was dropwise charged with 0.33 equivalents of POCl 3 .
  • Step A Preparation of tert-butyl (4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate: 2-bromo-1,4-difluorobenzene (1.5 eq.) was dissolved in 4 volumes of THF (based on weight of tert-butyl 2-oxopyrrolidine-1-carboxylate) and cooled to about 5° Celsius. A solution of 2.0 M iPrMgCl in THF (1.4 eq.) was added over 2 hours to the mixture while maintaining a reaction temperature below 25° Celsius. The solution was allowed to cool to about 5° Celsius and stirred for 1 hour (GC analysis confirmed Grignard formation).
  • the organic layer was washed with 4 volumes of saturated aqueous NaCl followed by addition of 2 x 1 volume of saturated aqueous NaCl.
  • the organic layer was solvent-switched to heptane ( ⁇ 1%wt THF confirmed by GC) at a distillation temperature of 35-55° Celsius and distillation pressure of 100-200 mm Hg for 2 x 4 volumes of heptane being added with a minimum distillation volume of about 7 volumes.
  • the mixture was then diluted to 10 volumes with heptane while heating to about 55° Celsius yielded a denser solid with the mixture being allowed to cool to room temperature overnight.
  • the slurry was cooled to less than 5° Celsius and filtered through polypropylene filter cloth.
  • Step B Preparation of 5-(2,5-difluorophenyl)-3,4-dihydro-2J/-pyrrole : tert -butyl (4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate was dissolved in 5 vol. of toluene with 2.2 eq. of 12M HCl being added observing a mild exotherm and gas evolution. The reaction was heated to 65° Celsius for 12-24 hours and monitored by HPLC. Upon completion the reaction was cooled to less than 15° Celsius with an ice/water bath. The pH was adjusted to about 14 with 3 equivalents of 2M aqueous NaOH (4.7 vol.).
  • the reaction was stirred at room temperature for 1-2 hours.
  • the mixture was transferred to a separatory funnel with toluene.
  • the aqueous layer was removed and the organic layer was washed with 3 volumes of saturated aqueous NaCl.
  • the organic layer was concentrated to an oil and redissolved in 1.5 volumes of heptane.
  • the resulting suspension was filtered through a GF/F filter paper and concentrated to a light yellow oil of 5-(2,5-difluorophenyl)-3,4-dihydro-2 H -pyrrole with a 90% to 100% theoretical yield.
  • Step C Preparation of ( R )-2-(2,5-difluorophenyl)pyrrolidine : Chloro-1,5-cyclooctadiene iridium dimer (0.2 mol%) and ( R )-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole (0.4 mol%) were suspended in 5 volumes of MTBE (based on 5-(2,5-difluorophenyl)-3,4-dihydro-2 H -pyrrole) at room temperature. The mixture was stirred for 1 hour and most of the solids dissolved with the solution turning dark red. The catalyst formation was monitored using an HPLC/PDA detector.
  • reaction was cooled to less than 5° Celsius and 5-(2,5-difluorophenyl)-3,4-dihydro-2 H -pyrrole (1.0 eq.) was added using a 0.5 volumes of MTBE rinse.
  • Diphenylsilane (1.5 eq.) was added over about 20 minutes while maintaining a reaction temperature below 10° Celsius.
  • the reaction was stirred for 30 minutes below 10° Celsius and then allowed to warm to room temperature.
  • the reaction was stirred overnight at room temperature.
  • the completion of the reaction was confirmed by HPLC and then cooled to less than 5° Celsius.
  • the reaction was quenched with 5 volumes of 2M aqueous HCl maintaining temperature below 20° Celsius.
  • Step D Preparation of (R)-2-(2,5-difluorophenyl)pyrrolidine ( R )-2-hydroxy-succinate :
  • ( R )-2-(2,5-difluorophenyl)pyrrolidine (1.0 eq.) was transferred to a round bottom flask charged with 15 volumes (corrected for potency) of EtOH (200 prf).
  • D-malic acid (1.05 eq.) was added and the mixture was heated to 65° Celsius. The solids all dissolved at about 64° Celsius. The solution was allowed to cool to RT.
  • suitable bases include tertiary amine bases, such as triethylamine, and K 2 CO 3 .
  • Suitable solvents include ethanol, heptane and tetrahydrofuran (THF). The reaction is conveniently performed at temperatures between 5° Celsius and 50° Celsius. The reaction progress was generally monitored by HPLC TRK1PM1.
  • the dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5:95 w/w solution of water/2-butanone (total weight 41652 g).
  • the mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed.
  • the slurry was filtered, and the filter cake was washed with a 5:95 w/w solution of water/2-butanone.
  • Compound I-HS i.e., the hydrogen sulfate salt of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide.
  • Eligibility criteria included age 1-21 years regardless of the presence of a known TRK alteration, as well as those patients aged 1 month of age or greater with a known NTRK fusion and a diagnosis of infantile fibrosarcoma or congential mesoblastic nephroma.
  • An oral liquid formulation of Compound I-HS was developed for patients unable to swallow capsules.
  • SIMCYP ® Pediatric Simulation modeling (CERTARA, Princeton, New Jersey) was utilized to establish a pharmacokinetic approach for dosing that takes into account patient age, ontogeny of the clearance pathways that eliminate Compound I-HS, and body surface area (BSA).
  • the pediatric dose selected for the initial cohort was predicted to equal the exposure achieved in adult patients taking a dose of 100 mg BID, the recommended Phase 2 adult dose. Cycles are measured in 28-day increments with continuous dosing. Response assessments by appropriate imaging modalities are scheduled every eight weeks. Patients continue on therapy until evidence of disease progression or intolerable toxicity.
  • a kit was provided that included a sealed graduated amber bottle containing 7.6 g of Compound I-HS; a sealed bottle containing 51 g CAVASOL ® W7 HP Pharma; a sealed bottle containing 500 g trisodium citrate dihydrate; a sealed bottle containing 100 mL sterile water; a sealed pint ( ⁇ 473 mL) bottle of ORA-Sweet ® SF; a funnel; a 28-mm press-in bottle adaptor; a box containing 56 units of 1-mL single use dosing syringes; a box containing 56 units of 5-mL single use dosing syringes; a drug product label indicating the concentration of Compound I-HS (20 mg/mL); and compounding instructions.
  • a liquid solution was prepared as shown in Figure 9 .
  • the seal (cap) was removed from the bottle containing CAVASOL ® W7 HP Pharma.
  • the funnel the contents of the 100 mL bottle of sterile water to were added to the bottle containing CAVASOL ® W7 HP Pharma.
  • the bottle with its cap was then closed and the bottle containing CAVASOL ® W7 HP Pharma and sterile water was shaken until all of the CAVASOL ® W7 HP was dissolved.
  • Ten minutes was allowed to pass for full dissolution of the CAVASOL ® W7 HP Pharma.
  • the bottom and sides of the bottle were inspected to make sure all CAVASOL ® W7 HP Pharma dissolved and was not clumped on the bottom or clinging to the sides.
  • the bottle was allowed to stand without agitation for approximately five minutes to allow the bubbles created from dissolved CAVASOL ® W7 HP Pharma to dissipate.
  • the seal (cap) from the graduated bottle containing Compound I-HS was then removed.
  • the CAVASOL ® W7 HP Pharma solution was added to the graduated bottle containing Compound I-HS.
  • the bottle was capped and shaken by hand until dissolved. Bubbles were allowed to come to surface and a clear red solution resulted.
  • Using the same funnel from earleir q.s. to 300 mL with the supplied ORA-Sweet ® SF.
  • the graduated bottle was capped and gently inverted 10 times to mix the ORA-Sweet ® SF with the Compound I-HS /CAVASOL ® W7 HP solution while being careful not to introduce too many bubbles into the formulation.
  • 3.5 g trisodium citrate dihydrate from the provided container of Trisodium Citrate Dihydrate was weighed and added, using the second funnel in the kit, to the liquid formulation and, subsequently, the bottle was capped and the bottle was inverted ten times. The bubbles were allowed to rise to the top and the contents of the bottle were inspected to make sure all of the trisodium citrate dihydrate was fully dissolved; if it was not, the bottle was inverted an additional 10 times.
  • the cap on the graduated bottle was removed and the provided 28-mm press-in bottle adaptor (syringe adaptor) was inserted in the bottle.
  • the bottle was then closed by securely placing the cap on the bottle.
  • the liquid formulation was then administered the desired amount of Compound I-HS using a 1mL or 5mL syringe, depending on patient dosing regimen.
  • a new chemotherapy regimen comprised of ifosfamide and doxorubicin (ID) was started concurrently with debulking surgery and a tracheostomy was placed-for oropharyngeal obstruction. Two additional courses of ID and four courses of ifosfamide and etoposide had minimal impact on the tumor. The tumor progressed to involve the base of skull, mastoids and cervical vasculature. Gross surgical resection was performed in October 2015 by a team of multidisciplinary surgeons but clear surgical margins could not be achieved.
  • ID doxorubicin
  • an MR of the brain and neck showed a 20mm ⁇ 19 mm ⁇ 18 mm hyperenhancing mass involving the skull base of the middle cranial fossa, just anterior and inferior to the inner ear structures (see Figure 10A and Figure 10B ).
  • Further chemotherapy was determined to be futile due to lack of response to all standard regimens. Repeat surgical resection was deemed not possible.
  • Therapeutic radiotherapy was possible, but based on the age of the patient and location of the disease, it was expected to produce devastating long-term sequelae.
  • a liquid formulation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide was prepared with the components listed in Table 16. Table 16.

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Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT2725028T (pt) 2008-10-22 2016-08-31 Array Biopharma Inc Compostos de pirazolo[1,5-]pirimidina substituídos como intermediários na síntese de inibidores de cinase trk
EP3368039A1 (en) 2015-10-26 2018-09-05 The Regents of The University of Colorado, A Body Corporate Point mutations in trk inhibitor-resistant cancer and methods relating to the same
RS65987B1 (sr) 2016-04-04 2024-10-31 Loxo Oncology Inc Tečne formulacije (s)-n-(5-((r)-2-(2,5-difluorofenil)-pirolidin-1-il)-pirazolo[1,5-]pirimidin-3-il)-3-hidroksipirolidin-1-karboksamida
EP3800189B1 (en) 2016-05-18 2023-06-28 Loxo Oncology, Inc. Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
JOP20190092A1 (ar) 2016-10-26 2019-04-25 Array Biopharma Inc عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها
CN109354578A (zh) * 2018-12-06 2019-02-19 浙江师范大学 一种替尼中间体以及替尼的合成方法
CN109593803A (zh) * 2018-12-24 2019-04-09 上海健康医学院 (r)-2-(2,5-二氟苯基)吡咯烷或其盐的制备方法
CN110283858B (zh) * 2019-07-05 2024-01-26 尚科生物医药（上海）有限公司 生物催化制备(s)-2-(2,5-二氟苯基)吡咯烷的方法
CN110804059B (zh) * 2019-09-30 2024-03-12 郑州泰基鸿诺医药股份有限公司 氨基甲酸酯类化合物、药物组合物及其应用
CN111302997B (zh) * 2020-04-15 2022-03-29 江苏恒沛药物科技有限公司 “一锅法”制备拉罗替尼中间体的方法
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017075107A1 (en) * 2015-10-26 2017-05-04 Nanda Nisha Point mutations in trk inhibitor-resistant cancer and methods relating to the same

Family Cites Families (125)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5844092A (en) 1994-03-18 1998-12-01 Genentech, Inc. Human TRK receptors and neurotrophic factor inhibitors
US5877016A (en) 1994-03-18 1999-03-02 Genentech, Inc. Human trk receptors and neurotrophic factor inhibitors
PL208113B1 (pl) 2000-06-22 2011-03-31 Genentech Inc Agonistyczne przeciwciało monoklonalne anty-trkC, mysie agonistyczne przeciwciało monoklonalne, ludzkie agonistyczne przeciwciało monoklonalne, wyizolowana cząsteczka kwasu nukleinowego kodująca mysie agonistyczne przeciwciało monoklonalne, wyizolowana cząsteczka kwasu nukleinowego kodująca ludzkie przeciwciało anty-trkC, cząsteczka kwasu nukleinowego, linia komórek gospodarza, linia komórek hybrydomy, przeciwciało wytwarzane przez tę linię komórek hybrydomy, wyizolowana cząsteczka kwasu nukleinowego i wektor zawierający tę cząsteczkę kwasu nukleinowego, przeciwciało, polipeptyd, kompozycja
ITMI20021620A1 (it) 2002-07-23 2004-01-23 Novuspharma Spa Composto ad ativita' antitumorale
US7514446B2 (en) 2003-02-20 2009-04-07 Smithkline Beecham Corporation Pyrimidine compounds
US20060094699A1 (en) 2003-04-11 2006-05-04 Kampen Gita Camilla T Combination therapy using an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist to minimize the side effects associated with glucocorticoid receptor agonist therapy
EP1682564A1 (en) 2003-10-27 2006-07-26 Genelabs Technologies, Inc. METHODS FOR PREPARING 7-(2 -SUBSTITUTED-s-D-RIBOFURANO SYL)-4-(NR2R3)-5-(SUBSTITUTED ETHYN-1-YL)-PYRROLO 2,3-D|PYRIMIDINE DERIVATIVES
MY141220A (en) 2003-11-17 2010-03-31 Astrazeneca Ab Pyrazole derivatives as inhibitors of receptor tyrosine kinases
RU2006122853A (ru) 2003-11-28 2008-01-10 Новартис АГ (CH) Производные диарилмочевины для лечения заболеваний, зависимых от протеинкиназы
PT1696920E (pt) 2003-12-19 2015-01-14 Plexxikon Inc Compostos e métodos para o desenvolvimento de moduladores de ret
WO2005068424A1 (en) 2004-01-20 2005-07-28 Cell Therapeutics Europe S.R.L. Indolinone derivatives as receptor tyrosine kinase ihibitors
US20050222171A1 (en) 2004-01-22 2005-10-06 Guido Bold Organic compounds
GB0512324D0 (en) 2005-06-16 2005-07-27 Novartis Ag Organic compounds
PE20060664A1 (es) 2004-09-15 2006-08-04 Novartis Ag Amidas biciclicas como inhibidores de cinasa
DE102005003687A1 (de) 2005-01-26 2006-07-27 Sphingo Tec Gmbh Immunoassay zur Bestimmung der Freisetzung von Neurotensin in die Zirkulation
AU2006215394B2 (en) 2005-02-16 2009-10-08 Astrazeneca Ab Chemical compounds
JP2008540335A (ja) 2005-04-27 2008-11-20 アストラゼネカ・アクチエボラーグ ピラゾリル・ピリミジン誘導体の疼痛治療における使用
US20080287437A1 (en) 2005-05-16 2008-11-20 Astrazeneca Ab Pyrazolylaminopyrimidine Derivatives Useful as Tyrosine Kinase Inhibitors
ITRM20050290A1 (it) 2005-06-07 2006-12-08 Lay Line Genomics Spa Uso di molecole in grado di inibire il legame tra ngf e il suo recettore trka come analgesici ad effetto prolungato.
PL1893612T3 (pl) 2005-06-22 2012-01-31 Plexxikon Inc Pochodne pirolo-[2,3-b]pirydyny jako inhibitory kinazy białkowej
HRP20140218T4 (hr) 2005-08-25 2017-06-16 Creabilis Therapeutics S.P.A. Polimerni konjugati k-252a i njihovi derivati
WO2007057399A2 (en) 2005-11-15 2007-05-24 Boehringer Ingelheim International Gmbh Treatment of cancer with indole derivatives
US8399442B2 (en) 2005-12-30 2013-03-19 Astex Therapeutics Limited Pharmaceutical compounds
US20090227598A1 (en) 2006-01-24 2009-09-10 Buser-Doepner Carolyn A Ret Tyrosine Kinase Inhibition
MX2008012422A (es) 2006-03-27 2008-10-09 Nerviano Medical Sciences Srl Derivados de furano y tiofeno, pirrol substituido con pirimidinil y piridil como inhibidores de cinasa.
CA2652442C (en) 2006-05-18 2014-12-09 Eisai R & D Management Co., Ltd. Antitumor agent for thyroid cancer
US20110195072A1 (en) 2006-09-12 2011-08-11 Anne Boulay Non-neuroendocrine cancer therapy
MX2009003185A (es) 2006-09-29 2009-04-03 Novartis Ag Pirazolopirimidinas como inhibidores de lipido cinasa pi3k.
CN101600718B (zh) 2006-11-06 2013-07-03 特雷罗药物股份有限公司 咪唑并[1,2-b]哒嗪和吡唑并[1,5-a]嘧啶衍生物及其作为蛋白激酶抑制剂的用途
PE20121126A1 (es) 2006-12-21 2012-08-24 Plexxikon Inc Compuestos pirrolo [2,3-b] piridinas como moduladores de quinasa
JP2010514695A (ja) 2006-12-21 2010-05-06 プレキシコン，インコーポレーテッド キナーゼ調節のための化合物および方法およびそのための適応症
WO2008079909A1 (en) 2006-12-21 2008-07-03 Plexxikon, Inc. Pyrrolo [2,3-b] pyridines as kinase modulators
US20080234267A1 (en) 2007-03-20 2008-09-25 Karen Elizabeth Lackey Compounds and Methods of Treatment
JP5160637B2 (ja) 2007-05-04 2013-03-13 アイアールエム・リミテッド・ライアビリティ・カンパニー ｃ−ｋｉｔおよびＰＤＧＦＲキナーゼインヒビターとしての化合物および組成物
AU2008273889B2 (en) 2007-07-09 2012-03-08 Astrazeneca Ab Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases
BRPI0814423B1 (pt) 2007-07-17 2022-04-19 Plexxikon, Inc Compostos que modulam quinase e composição farmacêutica compreendendo os mesmos
AU2008279776B2 (en) 2007-07-19 2013-05-23 Merck Sharp & Dohme Corp. Heterocyclic amide compounds as protein kinase inhibitors
US8299057B2 (en) 2007-07-20 2012-10-30 Nerviano Medical Sciences S.R.L. Substituted indazole derivatives active as kinase inhibitors
WO2009017838A2 (en) 2007-08-01 2009-02-05 Exelixis, Inc. Combinations of jak-2 inhibitors and other agents
JP2011501760A (ja) 2007-10-23 2011-01-13 ノバルティス アーゲー 呼吸器疾患の処置のためのｔｒｋｂ抗体の使用
WO2009071480A2 (en) 2007-12-04 2009-06-11 Nerviano Medical Sciences S.R.L. Substituted dihydropteridin-6-one derivatives, process for their preparation and their use as kinase inhibitors
AU2009205937B2 (en) 2008-01-17 2013-02-07 Novartis Ag Improved anti-TrkB antibodies
US20090227556A1 (en) 2008-01-31 2009-09-10 Eisai R&D Management Co., Ltd. Receptor tyrosine kinase inhibitors comprising pyridine and pyrimidine derivatives
EP2254886B1 (en) 2008-03-28 2016-05-25 Nerviano Medical Sciences S.r.l. 3,4-dihydro-2h-pyrazino[1,2-a]indol-1-one derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
PE20091846A1 (es) 2008-05-19 2009-12-16 Plexxikon Inc DERIVADOS DE PIRROLO[2,3-d]-PIRIMIDINA COMO MODULADORES DE CINASAS
WO2009143018A2 (en) 2008-05-19 2009-11-26 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
KR101257158B1 (ko) 2008-05-23 2013-04-23 노파르티스 아게 단백질 티로신 키나제 억제제로서의 퀴놀린 및 퀴녹살린의 유도체
EP2313411A1 (en) 2008-06-10 2011-04-27 Plexxikon, Inc. 5h-pyrr0l0 [2,3-b]pyrazine derivatives for kinase modulation, and indications therefor
WO2010012733A1 (en) 2008-07-29 2010-02-04 Nerviano Medical Sciences S.R.L. Use of a cdk inhibitor for the treatment of glioma
WO2010031816A1 (en) 2008-09-19 2010-03-25 Nerviano Medical Sciences S.R.L. 3,4 DIHYDRO-2H-PYRROLO[1,2-a]PYRAZIN-1-ONE DERIVATIVES
RS53350B (sr) 2008-09-22 2014-10-31 Array Biopharma, Inc. Supstituisana jedinjenja imidazo[1,2-b]piridazina kao inhibitori trk kinaze
PT2725028T (pt) 2008-10-22 2016-08-31 Array Biopharma Inc Compostos de pirazolo[1,5-]pirimidina substituídos como intermediários na síntese de inibidores de cinase trk
WO2010058006A1 (en) 2008-11-24 2010-05-27 Nerviano Medical Sciences S.R.L. Cdk inhibitor for the treatment of mesothelioma
JO3265B1 (ar) 2008-12-09 2018-09-16 Novartis Ag مثبطات بيريديلوكسى اندولات vegf-r2 واستخدامها لعلاج المرض
WO2010111527A1 (en) 2009-03-26 2010-09-30 Plexxikon, Inc. Pyrazolo [ 3, 4 -b] pyridines as kinase inhibitors and their medical use
US8546413B2 (en) 2009-06-15 2013-10-01 Nerviano Medical Sciences S.R.L. Substituted pyrimidinylpyrrolopyridinone derivatives, process for their preparation and their use as kinase inhibitors
AR077468A1 (es) 2009-07-09 2011-08-31 Array Biopharma Inc Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa
WO2011092120A1 (en) 2010-01-29 2011-08-04 Nerviano Medical Sciences S.R.L. 6,7- dihydroimidazo [1,5-a] pyrazin-8 (5h) - one derivatives as protein kinase modulators
TWI619713B (zh) 2010-04-21 2018-04-01 普雷辛肯公司 用於激酶調節的化合物和方法及其適應症
HUE044025T2 (hu) 2010-05-20 2019-09-30 Array Biopharma Inc Makrociklusos vegyületek mint TRK-kináz inhibitorok
WO2012034095A1 (en) 2010-09-09 2012-03-15 Irm Llc Compounds and compositions as trk inhibitors
UY33597A (es) 2010-09-09 2012-04-30 Irm Llc Compuestos y composiciones como inhibidores de la trk
JP2014005206A (ja) 2010-10-22 2014-01-16 Astellas Pharma Inc アリールアミノヘテロ環カルボキサミド化合物
EP2668188B1 (en) 2011-01-26 2016-05-18 Nerviano Medical Sciences S.r.l. Tricyclic derivatives, process for their preparation and their use as kinase inhibitors
RU2591191C2 (ru) 2011-01-26 2016-07-10 НЕРВИАНО МЕДИКАЛ САЙЕНСИЗ С.р.л. Трициклические пирроло производные, способ их получения и их применение в качестве ингибиторов киназы
CN103517710B (zh) 2011-02-07 2017-05-31 普莱希科公司 用于激酶调节的化合物
BR112013021537B1 (pt) 2011-02-24 2021-08-10 Nerviano Medical Sciences S.R.L. Derivados de tiazolilpenil-benzenosulfonamido como inibidores da quinase
GEP20156285B (en) 2011-02-25 2015-05-11 Aierem Elelsi Compounds and compositions as trk inhibitors
WO2012139930A1 (en) 2011-04-11 2012-10-18 Nerviano Medical Sciences S.R.L. Pyrazolyl-pyrimidine derivatives as kinase inhibitors
WO2012143248A1 (en) 2011-04-19 2012-10-26 Nerviano Medical Sciences S.R.L. Substituted pyrimidinyl-pyrroles active as kinase inhibitors
JP6396210B2 (ja) 2011-05-12 2018-09-26 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ キナーゼ阻害剤として活性な置換インダゾール誘導体
UA114711C2 (uk) 2011-05-13 2017-07-25 Еррей Біофарма Інк. Сполуки піролідинілсечовини й піролідинілтіосечовини як інгібітори кінази trka
US8912200B2 (en) 2011-07-28 2014-12-16 Nerviano Medical Sciences S.R.L. Alkynyl substituted pyrimidinyl-pyrroles active as kinases inhibitors
WO2013050446A1 (en) 2011-10-07 2013-04-11 Nerviano Medical Sciences S.R.L. SUBSTITUTED 3,4-DIHYDROPYRROLO[1,2-a]PYRAZIN-1(2H)-ONE DERIVATIVES AS KINASES INHIBITORS
EP2788350B1 (en) 2011-10-07 2017-12-06 Nerviano Medical Sciences S.r.l. 4-ALKYL SUBSTITUTED 3,4-DIHYDROPYRROLO[1,2-a]PYRAZIN-1(2H)-ONE DERIVATIVES AS KINASES INHIBITORS
WO2013059740A1 (en) 2011-10-21 2013-04-25 Foundation Medicine, Inc. Novel alk and ntrk1 fusion molecules and uses thereof
MX2014005632A (es) 2011-11-14 2014-10-17 Tesaro Inc Modulacion de ciertas cinasas de tirosina.
US8377946B1 (en) 2011-12-30 2013-02-19 Pharmacyclics, Inc. Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors
WO2013161919A1 (ja) 2012-04-26 2013-10-31 小野薬品工業株式会社 Ｔｒｋ阻害化合物
NZ716487A (en) 2012-05-23 2017-01-27 Nerviano Medical Sciences Srl Process for the preparation of n-[5-(3,5-difluoro-benzyl)-1h-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide
TWI585088B (zh) 2012-06-04 2017-06-01 第一三共股份有限公司 作爲激酶抑制劑之咪唑并［１，２－ｂ］嗒衍生物
RU2679130C2 (ru) 2012-07-11 2019-02-06 Блюпринт Медсинс Корпорейшн Ингибиторы рецептора фактора роста фибробластов
RU2666538C2 (ru) 2012-08-02 2018-09-11 НЕРВИАНО МЕДИКАЛ САЙЕНСИЗ С.р.л. Замещенные пирролы, активные в качестве ингибиторов киназ
ES2726605T3 (es) 2012-09-07 2019-10-08 Exelixis Inc Inhibidores de MET, VEGFR y RET para usar en el tratamiento del adenocarcinoma de pulmón
EP2914621B1 (en) * 2012-11-05 2023-06-07 Foundation Medicine, Inc. Novel ntrk1 fusion molecules and uses thereof
CN104870446B (zh) 2012-11-07 2019-08-13 内尔维阿诺医学科学有限公司 取代的嘧啶基和吡啶基吡咯并吡啶酮类、其制备方法及其作为激酶抑制剂的用途
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
HRP20161613T1 (hr) 2012-11-13 2017-01-13 Array Biopharma, Inc. Tvari bicikličke ureje, tioureje, gvanidina i cijanogvanidina korisne za liječenje boli
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078328A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. N-bicyclic aryl,n'-pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
WO2014078378A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078331A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
EP2922844B1 (en) 2012-11-13 2018-01-10 Array Biopharma, Inc. N-pyrrolidinyl, n'-pyrazolyl- urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
EP2960234B1 (en) 2013-02-19 2018-12-19 ONO Pharmaceutical Co., Ltd. Trk-inhibiting compound
US9499522B2 (en) 2013-03-15 2016-11-22 Blueprint Medicines Corporation Compositions useful for treating disorders related to kit
US8937071B2 (en) 2013-03-15 2015-01-20 Glaxosmithkline Intellectual Property Development Limited Compounds as rearranged during transfection (RET) inhibitors
JP6397897B2 (ja) 2013-05-14 2018-09-26 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ ピロロ［２，３−ｄ］ピリミジン誘導体、その製造方法及びキナーゼ阻害剤としてのその使用
RU2015149937A (ru) 2013-05-30 2017-07-06 Плексксикон Инк. Соединения для модулирования киназы и показания к их применению
WO2015017528A1 (en) 2013-07-30 2015-02-05 Blueprint Medicines Corporation Pik3c2g fusions
EP3027655B1 (en) 2013-07-30 2019-08-21 Blueprint Medicines Corporation Ntrk2 fusions
WO2015039006A1 (en) * 2013-09-16 2015-03-19 The General Hospital Corporation Methods of treating cancer
US9334263B2 (en) 2013-10-17 2016-05-10 Blueprint Medicines Corporation Compositions useful for treating disorders related to kit
SG11201602937UA (en) 2013-10-17 2016-05-30 Blueprint Medicines Corp Compositions useful for treating disorders related to kit
EP3060560A1 (en) 2013-10-25 2016-08-31 Blueprint Medicines Corporation Inhibitors of the fibroblast growth factor receptor
US9695165B2 (en) 2014-01-15 2017-07-04 Blueprint Medicines Corporation Inhibitors of the fibroblast growth factor receptor
CN110317214B (zh) 2014-01-24 2022-11-22 特普医药公司 作为蛋白质激酶的调节剂的二芳基巨环
WO2015120136A1 (en) 2014-02-05 2015-08-13 VM Oncology LLC Compositions of compounds and uses thereof
TWI672141B (zh) 2014-02-20 2019-09-21 美商醫科泰生技 投予ｒｏｓ１突變癌細胞之分子
US20170044622A1 (en) 2014-04-18 2017-02-16 Blueprint Medicines Corporation Pik3ca fusions
WO2015161277A1 (en) 2014-04-18 2015-10-22 Blueprint Medicines Corporation Met fusions
RU2719489C2 (ru) 2014-05-15 2020-04-17 Эррэй Биофарма Инк. 1-((3S,4R)-4-(3-ФТОРФЕНИЛ)-1-(2-МЕТОКСИЭТИЛ)ПИРРОЛИДИН-3-ИЛ)-3-(4-МЕТИЛ-3-(2-МЕТИЛПИРИМИДИН-5-ИЛ)-1-ФЕНИЛ-1Н-ПИРАЗОЛ-5-ИЛ)МОЧЕВИНА В КАЧЕСТВЕ ИНГИБИТОРА TrkA КИНАЗЫ
WO2015191666A2 (en) 2014-06-10 2015-12-17 Blueprint Medicines Corporation Raf1 fusions
EP3155118A1 (en) 2014-06-10 2017-04-19 Blueprint Medicines Corporation Pkn1 fusions
US10370725B2 (en) 2014-07-17 2019-08-06 Blueprint Medicines Corporation FGR fusions
US10370723B2 (en) 2014-07-17 2019-08-06 Blueprint Medicines Corporation TERT fusions
WO2016011147A1 (en) 2014-07-17 2016-01-21 Blueprint Medicines Corporation Prkc fusions
US9688680B2 (en) 2014-08-04 2017-06-27 Blueprint Medicines Corporation Compositions useful for treating disorders related to kit
TWI560185B (en) 2014-08-18 2016-12-01 Ono Pharmaceutical Co Acid addition salt of trk inhibitor compound
AU2015345054B2 (en) 2014-11-14 2020-03-05 Nerviano Medical Sciences S.R.L. 6-amino-7-bicyclo-7-deaza-purine derivatives as protein kinase inhibitors
FI3699181T3 (fi) * 2014-11-16 2023-03-28 Array Biopharma Inc Kiteinen muoto (s)-n-(5-((r)-2-(2,5-diluorifenyyli)-pyrrolidin-1-yyli)-pyratsolo[1,5-a]pyrimidin-3-yyli)-3-hydroksipyrrolidiini-1-karboksamidivetyysulfaatista
EP3221700B1 (en) 2014-11-18 2022-06-22 Blueprint Medicines Corporation Prkacb fusions
EP3303382A4 (en) 2015-05-29 2018-12-19 Ignyta, Inc. Compositions and methods for treating patients with rtk mutant cells

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017075107A1 (en) * 2015-10-26 2017-05-04 Nanda Nisha Point mutations in trk inhibitor-resistant cancer and methods relating to the same

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